Materials and methods for the treatment of diabetes, hyperlipidemia, hypercholesterolemia, and atherosclerosis

ABSTRACT

The subject invention provides pharmaceutical compounds useful in the treatment of Type II diabetes. These compounds are advantageous because they are readily metabolized by the metabolic drug detoxification systems. Particularly, thiazolidinedione analogs that have been designed to include esters within the structure of the compounds are provided. This invention is also drawn to methods of treating disorders, such as diabetes, comprising the administration of therapeutically effective compositions comprising compounds that have been designed to be metabolized by serum or intracellular hydrolases and esterases. Pharmaceutical compositions of the ester-containing thiazolidinedione analogs are also taught.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to United States ProvisionalApplications 60/199,146, filed Apr. 24, 2000; 60/234,423, filed Sep. 21,2000; 60/281,982, filed Apr. 6, 2001; and 60/314,792, filed Aug. 24,2001. This application is also a continuation-in-part of U.S. patentapplication Ser. No. 09/841,351, pending, filed Apr. 24, 2001. Thedisclosure of each of the above-identified applications is herebyincorporated by reference in their entireties, including all figures,tables, and chemical structures.

BACKGROUND OF THE INVENTION

[0002] Diabetes is one of the most prevalent chronic disorders worldwidewith significant personal and financial costs for patients and theirfamilies, as well as for society. Different types of diabetes exist withdistinct etiologies and pathogeneses. For example, diabetes mellitus isa disorder of carbohydrate metabolism, characterized by hyperglycemiaand glycosuria and resulting from inadequate production or utilizationof insulin.

[0003] Noninsulin-dependent diabetes mellitus (NIDDM), often referred toas Type II diabetes, is a form of diabetes that occurs predominantly inadults who produce adequate levels of insulin but who have a defect ininsulin-mediated utilization and metabolism of glucose in peripheraltissues. Overt NIDDM is characterized by three major metabolicabnormalities: resistance to insulin-mediated glucose disposal,impairment of nutrient-stimulated insulin secretion, and overproductionof glucose by the liver. It has been shown that for some people withdiabetes a genetic predisposition results from a mutation in the gene(s)coding for insulin and/or the insulin receptor and/or insulin-mediatedsignal transduction factor(s), thereby resulting in ineffective insulinand/or insulin-mediated effects thus impairing the utilization ormetabolism of glucose.

[0004] For people with Type II diabetes, insulin secretion is oftenenhanced, presumably to compensate for insulin resistance. Eventually,however, the B-cells fail to maintain sufficient insulin secretion tocompensate for the insulin resistance. Mechanisms responsible for theB-cell failure have not been identified, but may be related to thechronic demands placed on the B-cells by peripheral insulin resistanceand/or to the effects of hyperglycemia. The B-cell failure could alsooccur as an independent, inherent defect in “pre-diabetic” individuals.

[0005] NIDDM often develops from certain at risk populations. One suchpopulation is individuals with polycystic ovary syndrome (PCOS). PCOS isthe most common endocrine disorder in women of reproductive age. Thissyndrome is characterized by hyperandrogenism and disorderedgonadotropin secretion producing oligo- or anovulation. Recentprevalence estimates suggest that 5-10% of women between 18-44 years ofage (about 5 million women, according to the 1990 census) have thefull-blown syndrome of hyperandrogenism, chronic anovulation, andpolycystic ovaries. Despite more than 50 years since its originaldescription, the etiology of the syndrome remains unclear. Thebiochemical profile, ovarian morphology, and clinical features arenon-specific; hence, the diagnosis remains one of exclusion ofdisorders, such as androgen-secreting tumors, Cushing's Syndrome, andlate-onset congenital adrenal hyperplasia. PCOS is associated withprofound insulin resistance resulting in substantial hyperinsulinemia.As a result of their insulin resistance, PCOS women are at increasedrisk to develop NIDDM.

[0006] NIDDM also develops from the at risk population of individualswith gestational diabetes mellitus (GDM). Pregnancy normally isassociated with progressive resistance to insulin-mediated glucosedisposal. In fact, insulin sensitivity is lower during late pregnancythan in nearly all other physiological conditions. The insulinresistance is thought to be mediated in large part by the effects ofcirculating hormones such as placental lactogen, progesterone, andcortisol, all of which are elevated during pregnancy. In the face of theinsulin resistance, pancreatic B-cell responsiveness to glucose normallyincreases nearly 3-fold by late pregnancy, a response that serves tominimize the effect of insulin resistance on circulating glucose levels.Thus, pregnancy provides a major “stress-test” of the capacity forB-cells to compensate for insulin resistance.

[0007] Other populations thought to be at risk for developing NIDDMinclude persons with Syndrome X; persons with concomitanthyperinsulinemia; persons with insulin resistance characterized byhyperinsulinemia and by failure to respond to exogenous insulin; andpersons with abnormal insulin and/or evidence of glucose disordersassociated with excess circulating glucocorticoids, growth hormone,catecholamines, glucagon, parathyroid hormone, and otherinsulin-resistant conditions.

[0008] Failure to treat NIDDM can result in mortality due tocardiovascular disease and in other diabetic complications includingretinopathy, nephropathy, and peripheral neuropathy. There is asubstantial need for a method of treating at risk populations such asthose with PCOS and GDM in order to prevent or delay the onset of NIDDMthereby bringing relief of symptoms, improving the quality of life,preventing acute and long-term complications, reducing mortality andtreating accompanying disorders of the populations at risk for NIDDM.

[0009] For many years, treatment of NIDDM has involved a program aimedat lowering blood sugar with a combination of diet and exercise.Alternatively, treatment of NIDDM can involve oral hypoglycemic agents,such as sulfonylureas alone or in combination with insulin injections.Recently, alpha-glucosidase inhibitors, such as a carboys, have beenshown to be effective in reducing the postprandial rise in blood glucose(Lefevre, et al., Drugs 1992; 44:29-38). In Europe and Canada anothertreatment used primarily in obese diabetics is metfornin, a biguanide.

[0010] Compounds useful in the treatment of the various disordersdiscussed above, and methods of making the compounds, are known and someof these are disclosed in U.S. Pat. Nos. 5,223,522 issued Jun. 29, 1993;5,132,317 issued Jul. 12, 1992; 5,120,754 issued Jun. 9, 1992; 5,061,717issued Oct. 29, 1991; 4,897,405 issued Jan. 30, 1990; 4,873,255 issuedOct. 10, 1989; 4,687,777 issued Aug. 18, 1987; 4,572,912 issued Feb. 25,1986; 4,287,200 issued Sep. 1, 1981; 5,002,953, issued Mar. 26, 1991;U.S. Pat. Nos. 4,340,605; 4,438,141; 4,444,779; 4,461,902; 4,703,052;4,725,610; 4,897,393; 4,918,091; 4,948,900; 5,194,443; 5,232,925; and5,260,445; WO 91/07107; WO 92/02520; WO 94/01433; WO 89/08651; and JPKokai 69383/92. The compounds disclosed in these issued patents andapplications are useful as therapeutic agents for the treatment ofdiabetes, hyperglycemia, hypercholesterolemia, and hyperlipidemia. Theteachings of these issued patents are incorporated herein by referencein their entireties.

[0011] Drug toxicity is an important consideration in the treatment ofhumans and animals. Toxic side effects resulting from the administrationof drugs include a variety of conditions that range from low-grade feverto death. Drug therapy is justified only when the benefits of thetreatment protocol outweigh the potential risks associated with thetreatment. The factors balanced by the practitioner include thequalitative and quantitative impact of the drug to be used as well asthe resulting outcome if the drug is not provided to the individual.Other factors considered include the physical condition of the patient,the disease stage and its history of progression, and any known adverseeffects associated with a drug.

[0012] Drug elimination is typically the result of metabolic activityupon the drug and the subsequent excretion of the drug from the body.Metabolic activity can take place within the vascular supply and/orwithin cellular compartments or organs. The liver is a principal site ofdrug metabolism. The metabolic process can be categorized into syntheticand nonsynthetic reactions. In nonsynthetic reactions, the drug ischemically altered by oxidation, reduction, hydrolysis, or anycombination of the aforementioned processes. These processes arecollectively referred to as Phase I reactions.

[0013] In Phase II reactions, also known as synthetic reactions orconjugations, the parent drug, or intermediate metabolites thereof, arecombined with endogenous substrates to yield an addition or conjugationproduct. Metabolites formed in synthetic reactions are, typically, morepolar and biologically inactive. As a result, these metabolites are moreeasily excreted via the kidneys (in urine) or the liver (in bile).Synthetic reactions include glucuronidation, amino acid conjugation,acetylation, sulfoconjugation, and methylation.

[0014] One of the drugs used to treat Type II diabetes is troglitazone.The major side effects of troglitazone are nausea, peripheral edema, andabnormal liver function. Other reported adverse events include dyspnea,headache, thirst, gastrointestinal distress, insomnia, dizziness,incoordination, confusion, fatigue, pruritus, rash, alterations in bloodcell counts, changes in serum lipids, acute renal insufficiency, anddryness of the mouth. Additional symptoms that have been reported, forwhich the relationship to troglitazone is unknown, include palpitations,sensations of hot and cold, swelling of body parts, skin eruption,stroke, and hyperglycemia. Accordingly, forms of glitazones which havefewer, or no, adverse effects (i.e., less toxicity) are desirable.

[0015] The principal difference between the compounds of the presentinvention and related compounds is the presence of a carboxyl group,either OOC- or COO-, directly attached to the 4-position of the phenylring. In the literature, thiazolidinediones having similar therapeuticproperties have an ether function at the 4-position of the phenyl ringinstead of a carboxyl group.

[0016] The presence of the carboxyl group has significant consequencesfor the biological behavior of these new compounds. The presentcompounds are primarily metabolized by hydrolytic enzymatic systems,whereas compounds having an ether function are metabolized only byoxidative enzymes. Hydrolytic enzymatic systems are ubiquitous,non-oxidative, not easily saturable, and non-inducible, and, therefore,reliable. By contrast, oxidative systems are mediated by the P-450isozymes. These systems are localized, mainly, in the liver, saturableand inducible (even at low concentrations of therapeutic compounds) andtherefore are highly unreliable.

[0017] The compounds of the subject invention do not rely on saturablehepatic systems for their metabolism and elimination, whereas the priorart compounds exert a heavy bio-burden on hepatic functions, especiallyin the presence of other drugs that rely on similar enzymes fordetoxification. Thus, the present compounds have a much more desirabletoxicity profile than prior art compounds, especially when consideringliver toxicity and potentially fatal drug-drug interactions.

[0018] Upon metabolism by plasma and tissue esterases, the compounds ofthis invention are hydrolyzed into 2 types of molecules: 1) an alcoholor a phenol, and 2) a carboxylic acid. Therefore, any compound thatyields compound 1, compound 2, compound 3, or compound 4, as defined inTable I, as a primary metabolite falls under the definition of thisinvention. This concept is illustrated in FIG. 1, taking compound 9 (ofTable I) and compound 145 (of Table X) as specific examples of compoundsgiving 1 and 3, respectively, upon non-oxidative metabolism byesterases.

BRIEF SUMMARY OF THE INVENTION

[0019] The subject invention provides materials and methods for the safeand effective treatment of diabetes, hyperlipidemia,hypercholesterolemia, and atherosclerosis. In a preferred embodiment,the subject invention provides therapeutic compounds for the treatmentof diabetes. The compounds of the subject invention can be used to treatat-risk populations, such as those with PCOS and GDM, in order toprevent or delay the onset of NIDDM thereby bringing relief of symptoms,improving the quality of life, preventing acute and long-termcomplications, reducing mortality and treating accompanying disorders.

[0020] Advantageously, the subject invention provides compounds that arereadily metabolized by the physiological metabolic drug detoxificationsystems. Specifically, in a preferred embodiment, the therapeuticcompounds of the subject invention contain an ester group, which doesnot detract from the ability of these compounds to provide a therapeuticbenefit, but which makes these compounds more susceptible to degradationby hydrolases, particularly serum and/or cytosolic esterases. Thesubject invention further provides methods of treatment comprising theadministration of these compounds to individuals in need of treatmentfor Type II diabetes, hyperlipidemia, hypercholesterolemia, andatherosclerosis.

[0021] In a further embodiment, the subject invention pertains to thebreakdown products that are formed when the therapeutic compounds of thesubject invention are acted upon by esterases. These breakdown productscan be used as described herein to monitor the clearance of thetherapeutic compounds from a patient.

[0022] In yet a further embodiment, the subject invention providesmethods for synthesizing the therapeutic compounds of the subjectinvention.

BRIEF DESCRIPTION OF THE FIGURES

[0023]FIG. 1 depicts exemplary metabolic breakdown products resultingfrom the actions of esterases on compounds of the invention.

[0024] FIGS. 2-3 provide an exemplary synthetic scheme for compounds 1through 4 (of Table I). These compounds can be conveniently prepared bythe Knoevenagel reaction between an aldehyde and thiazolidine-2,4-dioneusing, for example, sodium acetate in acetic anhydride, or piperidineand benzoic acid in methylene chloride as a reaction medium.

[0025]FIG. 4 illustrates an alternative reaction scheme for theproduction of compound 1 (of Table I). In this reaction scheme,para-anisidine undergoes a diazotation reaction with sodium nitrite andhydrochloric acid. The diazonium chloride salt undergoing, in turn, aradicalar reaction with methyl acrylate and then a cyclization reactionwith thiourea, the product of which is hydrolyzed to thethiazolidinedione molecule.

[0026]FIG. 5 shows an exemplary synthetic scheme for the compoundsdescribed in Table I (compounds 5 to 32). These compounds can be madevia an esterification reaction between 1 or 2 and an appropriatelysubstituted carboxylic acid, or between 3 or 4 and an appropriatelysubstituted alcohol.

[0027]FIG. 6 depicts the synthesis of the 4-oxazoleacetic acid and the4-oxazoleethanol moiety starting from aspartic acid derivatives in whichR₂ and R₃ are methyl or hydrogen.

[0028]FIG. 7 describes the synthesis of the 4-oxazolecarboxylic acid and4-oxazolemethanol groups. The synthesis starts from ethyl acetoacetatein which a 2-amino-group is introduced via oxime formation followed byreduction with zinc powder. The synthesis then proceeds as before, wherethe R₁ group is introduced by acylating the amino group, followed bycyclization with sulfuric acid in ethyl acetate, and finally estercleavage or reduction to the alcohol.

[0029]FIG. 8 shows how steric hindrance can be introduced under the formof methyl groups on the 4-methanol moiety. Starting frompentane-2,4-dione and following the same synthetic sequence as in FIG. 7leads to the 4-acetyloxazole compounds which can be reduced by sodiumborohydride to the 4-(1-ethyl)oxazole, or which can be transformed to4-(2-hydroxy-2-propyl) oxazole with a methyl Grignard reagent such asmethyl magnesium iodide.

[0030]FIG. 9 illustrates an alternative synthetic scheme whereincondensation of a thioamide with methyl 4-bromo-3-oxopentanoate givesmethyl 4-thiazoleacetate. Ester cleavage with lithium hydroxide orreduction with lithium aluminum hydride gives the corresponding acid orthe alcohol, respectively.

[0031] FIGS. 10-17 depict the synthesis of compounds 105 to 224 inTables VI to XVII. These compounds contain an amino acid or an aminoalcohol as part of their structure.

[0032]FIG. 18 provides an exemplary synthetic pathway for compounds 225to 242 (Table XVIII). These compounds are oxazoline-4-carboxylic acidtypes of compounds. Their synthesis (FIG. 18) starts from serine (R₅=H)or from threonine (R₅═CH₃) benzyl ester. The ester is coupled with analkyl or an arylcarboxylic acid using for example EDC as a couplingagent. The serine or threonine group then cyclizes into an oxazolineupon treatment with thionyl chloride. Coupling with5-(4-hydroxybenzyl)thiazolidine-2,4-dione using DCC/DMAP/methylenechloride gives compounds 225 to 242.

[0033] FIGS. 19-20 illustrate the activity of representative compoundson serum glucose and insulin levels in non-insulin dependent diabeticmellitus (NIDDM) KK-A^(y) male mice. Post-treatment data for each groupwere transferred to a percentage of pretreatment values and unpairedStudent's t test was used for comparison between vehicle and testsubstance treated groups. Results show a significant reduction of bothserum glucose and serum insulin relative to the vehicle control group.Reduction in serum glucose and serum insulin levels were comparable tothe reduction observed in the troglitazone-treated animals. The resultsare also presented in Table XXI.

[0034]FIG. 21 shows exemplary compounds of Formula IB.

[0035] FIGS. 22-28 show exemplary synthesis schemes to produce compoundsof Formula IB.

BRIEF DESCRIPTION OF THE TABLES

[0036] Tables I-XXII depict exemplary compounds according to theinvention. The term “db” indicates a double bond between P and Q.

[0037] Table XXIII illustrates the effects of exemplary compounds onserum glucose and insulin levels in NIDDM mice.

DETAILED DISCLOSURE OF THE INVENTION

[0038] The subject invention provides materials and methods for thetreatment of non-insulin dependent diabetes mellitus (NIDDM),hyperlipidemia, hypercholesterolemia, and atherosclerosis.Advantageously, the therapeutic compounds of the subject invention arestable in storage but have a shorter half-life in the physiologicalenvironment than other drugs which are available for treatment ofdiabetes; therefore, the compounds of the subject invention can be usedwith a lower incidence of side effects and toxicity, especially inpatients having elevated liver function or compromised liver function.

[0039] In a preferred embodiment of the subject invention, therapeuticcompounds are provided which are useful in the treatment of diabetes,hyperlipidemia, hypercholesterolemia, and atherosclerosis and whichcontain an ester group which is acted upon by esterases thereby breakingdown the compound and facilitating its efficient removal from thetreated individual. In a preferred embodiment the therapeutic compoundsare metabolized by the Phase I drug detoxification system and areexemplified by the compound of Formula I.

[0040] The compounds of Formula I can be generally described as5-benzyl- or 5-benzylidene-thiazolidine-2,4-dione compounds having acarboxyl group directly attached to the para-position of the phenylring. These compounds represent a new class of chemical compounds havingtherapeutic properties for the treatment of type-II diabetes mellitus,atherosclerosis, hypercholesterolemia, and hyperlipidemia.

[0041] For compounds of Formula I:

[0042] A and B may be the same or different and are CH₂, CO, N, NO, NH,SO₀₋₂, or O;

[0043] D₁-D₆ can be the same or different and are CH, N, S, or O;

[0044] E can be a substituent attached to one or more of the atomslocated at D₁-D₆;

[0045] P and Q can be a double bond; or

[0046] P, Q, and E can be the same or different and are a moietyselected from the group consisting of H, C₁₋₁₀ alkyl, substituted alkylgroups, substituted or unsubstituted carboxylic acids, substituted orunsubstituted carboxylic esters, halogen, carboxyl, hydroxyl, phosphate,phosphonate, aryl, CN, OH, COOH, NO₂, NH₂, SO₂₋₄, C₁₋₂₀ heteroalkyl,C₂₋₂₀ alkenyl, alkynyl, akynyl-aryl, alkynyl-heteroaryl, aryl, C₁₋₂₀alkyl-aryl, C₂₋₂₀ alkenyl-aryl, heteroaryl, C₁₋₂₀ alkyl-heteroaryl,C₂₋₂₀ alkenyl-heteroaryl, cycloalkyl, heterocycloalkyl, C₁₋₂₀alkyl-heteroycloalkyl, and C₁₋₂₀ alkyl-cycloalkyl, any of which may be,optionally, substituted with a moiety selected from the group consistingof C₁₋₆ alkyl, halogen, OH, NH₂, CN, NO₂, COOH, or SO₂₋₄. Exemplaryheterocyclic groups include, but not limited to, morpholine, triazole,imidazole, pyrrolidine, piperidine, piperazine, pyrrole,dihydropyridine, aziridine, thiazolidine, thiazoline, thiadiazolidine orthiadiazoline.

[0047] Substituted carboxylic acids, substituted carboxylic esters, andsubstituted alkyl groups can be substituted at any available positionwith a moiety selected from the group consisting of C₁₋₁₀ alkyl,halogen, CN, OH, COOH, NO₂, NH₂, SO₂₋₄, C₁₋₂₀ heteroalkyl, C₂₋₂₀alkenyl, alkynyl, akynyl-aryl, alkynyl-heteroaryl, aryl, C₁₋₂₀alkyl-aryl, C₂₋₂₀ alkenyl-aryl, heteroaryl, C₁₋₂₀ alkyl-heteroaryl,C₂₋₂₀ alkenyl-heteroaryl, cycloalkyl, heterocycloalkyl, C₁₋₂₀alkyl-heteroycloalkyl, and C₁₋₂₀ alkyl-cycloalkyl, any of which may be,optionally, substituted with a moiety selected from the group consistingof C₁₋₆ alkyl, halogen, OH, NH₂, CN, NO₂, COOH, or SO₂₋₄. Exemplaryheterocyclic groups include, but are not limited to, morpholine,triazole, imidazole, pyrrolidine, piperidine, piperazine, pyrrole,dihydropyridine, aziridine, thiazolidine, thiazoline, thiadiazolidine,and thiadiazoline.

[0048] X is —OH, —COOH, or a substituted carboxylic group having thecarboxyl moiety OOC— or COO— directly attached to the phenyl ring of thecompound of Formula 1. The carboxylic acid group can be substituted witha moiety selected from the group consisting of alkyloxycarbonyl,alkylcarbonyloxy, aryloxycarbonyl, arylcarbonyloxy,heteroalkyloxycarbonyl, heteroalkylcarbonyloxy, heteroaryl-oxycarbonyl,and heteroarylcarbonyloxy each of which is, optionally, substituted withC₁₋₁₀ alkyl, CN, COOH, NO₂, NH₂, SO₂₋₄, C₁₋₂₀ heteroalkyl, C₂₋₂₀alkenyl, alkynyl, akynyl-aryl, alkynyl-heteroaryl, aryl, C₁₋₂₀alkyl-aryl, C₂₋₂₀ alkenyl-aryl, heteroaryl, C₁₋₂₀ alkyl-heteroaryl,C₂₋₂₀ alkenyl-heteroaryl, cycloalkyl, heterocycloalkyl, C₁₋₂₀alkyl-heteroycloalkyl, and C₁₋₂₀ alkyl-cycloalkyl, any of which may be,optionally, substituted with a moiety selected from the group consistingof C₁₋₆ alkyl, halogen, OH, NH₂, CN, NO₂, COOH, or SO₂₋₄. In otherembodiments, the substituted carboxylic group can be substituted with amoiety selected from the group consisting of C₁₋₁₀ alkyl, CN, COOH, NO₂,NH₂, SO₂₋₄, C₁₋₂₀ heteroalkyl, C₂₋₂₀ alkenyl, alkynyl, akynyl-aryl,alkynyl-heteroaryl, aryl, C₁₋₂₀ alkyl-aryl, C₂₋₂₀ alkenyl-aryl,heteroaryl, C₁₋₂₀ alkyl-heteroaryl, C₂₋₂₀ alkenyl-heteroaryl,cycloalkyl, heterocycloalkyl, C₁₋₂₀ alkyl-heteroycloalkyl, and C₁₋₂₀alkyl-cycloalkyl, any of which may be, optionally, substituted with amoiety selected from the group consisting of C₁₋₆ alkyl, halogen, OH,NH₂, CN, NO₂, COOH, or SO₂₋₄. Exemplary heterocyclic groups include, butare not limited to, morpholine, triazole, imidazole, pyrrolidine,piperidine, piperazine, pyrrole, dihydropyridine, aziridine,thiazolidine, thiazoline, thiadiazolidine, and thiadiazoline.

[0049] In specific embodiments, X can be hydroxyl, hydroxycarbonyl,1-methyl-1-cyclohexylcarbonyloxy, 1-methyl-1-cyclohexylmethoxycarbonyl,5-ethyl-2-pyridyl-acetoxy, 5-ethyl-2-pyridylmeth-oxy-carbonyl,(R)-6-hydroxy-2,5,7,8-tetramethyl-chroman-2-carboxy,(S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxy,(R)-6-hydroxy-2,5,7,8-tetra-methylchroman-2-ylmethoxy -carbonyl,(S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxycarbonyl,(R)-5-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-3-carboxy,(S)-5-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-benzofuran-3-carboxy,(R)-5-hydroxy-2,2,4,6,7-penta-methyl-2,3-dihydrobenzofuran-3-methoxycarbonyl,(S)-5-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-3-methoxycarbonyl, 2-hydroxybenzoyloxy, or2,4-dihydroxybenzoyloxy.

[0050] In other embodiments, X can be

[0051] wherein Hetero is an aromatic, cyclic, or alicyclic moiety thatcan contain heteroatoms. In certain specific embodiments, Hetero is anaromatic, cyclic, or alicyclic moiety that contains heteroatoms that aregenerally part of the structure of the statin-family of lipid loweringagents. Preferred examples include, but are not limited to,2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1-(1H-pyrrol)yl, a component of atorvastatin, and1,2,3,7,8,8a-hexahydro-1-(2-methylbutanoyl)oxy-3,7-dimethyl-8-naphthalenyl,a component of lovastatin.

[0052] Alternatively, X can be

[0053] wherein Fib is an aromatic, cyclic, or alicyclic moiety that cancontain heteroatoms. In certain specific embodiments, Fib moieties arepart of the fibrate-family of lipid lowering agents. Preferred examplesinclude, but are not limited to 4-(4-chlorobenzoyl)phenoxy, a componentof fenofibric acid, 4-chlorophenoxy, a component of clofibric acid, and3-(2,5-xylyloxy)-l -propyl, a component of gemfibrozil.

[0054] Alternatively, X can be

[0055] wherein R is hydrogen or methyl, and in which NSAID means anaromatic, alkyl, or cycloalkyl moiety that may contain heteroatoms andthat are generally part of the family of non-steroidal anti-inflammatoryagents. Preferred examples include, but are not limited to4-(2-methyl-1-propyl)phenyl, 2-(2,6-dichloro-1-phenyl)aminophenyl,6′-methoxy-2′-naphthyl, and 6′-methoxy-2′-naphthylmethyl.

[0056] In another embodiment, X can be

[0057] where α and β are hydrogen or α and β form a bond, and where γ,δ, and ε, are independently hydrogen, hydroxy, fluoro, chloro, ormethyl.

[0058] Alternatively, X can be

[0059] X can also be of the general formula

[0060] In such embodiments, n is 0 or 1, R₂ and R₃ are independentlyhydrogen or methyl; Z is N, O, or S; and R₁ is aryl or heteroaryl, alkylor heteroalkyl. Preferred non-limiting examples include compounds whereR₁ is phenyl, 4-fluorophenyl, 4-methoxyphenyl, 3-methyl-2-thiophenyl,5-methyl-2-thiophenyl, 5-methyl-3-isoxazolyl, 2-pyridyl, 4-pyridyl,2-pyrazinyl, 2-hydroxybenzoyl, or 2,4-dihydroxybenzoyl.

[0061] Other embodiments provide compounds wherein X is

[0062] in which n is 0 or 1, R₂ and R₃ are independently hydrogen ormethyl; Z is N, O, or S; and R₁ is aryl or heteroaryl, alkyl orheteroalkyl. Preferred non-limiting examples include compounds where R1is phenyl, 4-fluorophenyl, 4-methoxyphenyl, 3-methyl-2-thiophenyl,5-methyl-2-thiophenyl, 5-methyl-3-isoxazolyl, 2-pyridyl, 4-pyridyl,2-pyrazinyl, 2-hydroxybenzoyl, or 2,4-dihydroxybenzoyl.

[0063] In other embodiments, X is a 1-substituted(R)-pyrrolidine-2-methoxycarbonyl, (S)-pyrrolidine-2-methoxycarbonyl,(R)-pyrrolidine-2-carboxy, or (S)-pyrrolidine-2-carboxy, having thefollowing formulas

[0064] in which Y is aryl or heteroaryl, alkyl or heteroalkyl. Preferrednon-limiting examples include compounds where Y is(R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxy,(S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxy,(R)-6-hydroxy-2,5,7,8-tetrameth-ylchroman-2-ylmeth-oxycarbonyl,(S)-6-hydroxy-2,5,7,8-tetra-methylchroman-2-ylmeth-oxycarbonyl,(R)-5-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-3-carboxy,(S)-5-hydroxy-2,2,4,6 ,7-pentamethyl-2,3-dihydro-benzofuran-3-carboxy,(R)-5-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-3-methoxycarbonyl,(S)-5-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-3-methoxycarbonyl,5-chloro-2-pyridyl, 5-methyl-2-pyridyl, 3-chloro-2-pyridyl,4-methyl-2-pyridyl, 2-pyridyl, 2-benzoxazolyl, 2-benzothiazolyl,5-amino-2-pyridyl, 5-nitro-2-pyridyl, 2-pyrazinyl,4-phenyl-2-oxazolinyl, 5-methyl-2-thiazolinyl,4,5-dimethyl-2-oxazolinyl, 4,5-dimethyl-2-thiazolinyl,5-phenyl-2-thiazolinyl, 2-thiazolinyl, 4-methyl-5-phenyl-2-thiazolinyl,5-methyl-4-phenyl-2-thiazolinyl, 2-piperidinyl, 4-phenyl-2-piperidinyl,6-methyl-2-pyridinyl, 6-methoxy-2-pyridinyl, 2-hydroxybenzoyl, or2,4-dihydroxybenzoyl.

[0065] Alternatively X is an N-substituted 2-methylaminoethoxycarbonylor a N-substituted 2-methylaminoacetoxy, having the following formulas:

[0066] in which Y is aryl or heteroaryl, alkyl or heteroalkyl. Preferrednon-limiting examples include compounds where Y is(R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxy,(S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxy,(R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmeth-oxycarbonyl,(S)-6-hydroxy-2,5,7,8-tetra-methylchroman-2-ylmethoxycarbonyl,(R)-5-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-3-carboxy,(S)-5-hydroxy-2,2,4,6, 7-pentamethyl-2,3-dihydro-benzofuran-3-carboxy,(R)-5-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-3-methoxycarbonyl,(S)-5-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-3-methoxycarbonyl,5-chloro-2-pyridyl, 5-methyl-2-pyridyl, 3-chloro-2-pyridyl,4-methyl-2-pyridyl, 2-pyridyl, 2-benzoxazolyl, 2-benzothiazolyl,5-amino-2-pyridyl, 5-nitro-2-pyridyl, 2-pyrazinyl,4-phenyl-2-oxazolinyl, 5-methyl-2-thiazolinyl,4,5-dimethyl-2-oxazolinyl, 4,5-dimethyl-2-thiazolinyl,5-phenyl-2-thiazolinyl, 2-thiazolinyl, 4-methyl-5-phenyl-2-thiazolinyl,5-methyl-4-phenyl-2-thiazolinyl, 2-piperidinyl, 4-phenyl-2-piperidinyl,6-methyl-2-pyridinyl, 6-methoxy-2-pyridinyl, 2-hydroxybenzoyl, or2,4-dihydroxybenzoyl.

[0067] X can also be a 1-substituted (R)-pyrrolidine-2-methoxycarbonyl,(S)-pyrrolidine-2-methoxycarbonyl, (R)-pyrrolidine-2-carboxy, or(S)-pyrrolidine-2-carboxy, having the following formulas:

[0068] wherein Y is

[0069] n is 0 or 1; R₂ and R₃ are independently hydrogen or methyl; Z isN, O, or S; and R₁ is aryl or heteroaryl, alkyl or heteroalkyl.Preferred non-limiting examples include compounds where R₁ is phenyl,4-fluorophenyl, 4-methoxyphenyl, 3-methyl-2-thiophenyl,5-methyl-2-thiophenyl, 5-methyl-3-isoxazolyl, 2-pyridyl, 4-pyridyl, or2-pyrazinyl; or

[0070] Y is

[0071] n is 0 or 1; m is 0 or 1; R₂ and R₃ are independently hydrogen ormethyl; Z is N, O, or S; and R₁ is aryl or heteroaryl, alkyl orheteroalkyl. Preferred non-limiting examples include compounds where R₁is phenyl, 4-fluorophenyl, 4-methoxyphenyl, 3-methyl-2-thiophenyl,5-methyl-2-thiophenyl, 5-methyl-3-isoxazolyl, 2-pyridyl, 4-pyridyl, or2-pyrazinyl; or

[0072] Y is

[0073] wherein Hetero is an aromatic, cyclic, or alicyclic moiety thatusually contains heteroatoms. In certain specific embodiments, thesemoieties are part of the structure of the statin-family of lipidlowering agents. Preferred examples include, but are not limited to,2-(4-fluorophenyl)-5-( 1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1-(lH-pyrrol)yl, acomponent of atorvastatin, and1,2,3,7,8,8a-hexahydro-1-(2-methylbutanoyl)oxy-3,7-dimethyl-8-naphthalenyl,a component of lovastatin; or

[0074] Y is

[0075] wherein Fib is an aromatic, cyclic, or alicyclic moiety thatcontains heteroatoms. In some embodiments, these moieties are part ofthe fibrate-family of lipid lowering agents. Preferred examples include,but are not limited to 4-(4-chlorobenzoyl)phenoxy, a component offenofibric acid, 4-chlorophenoxy, a component of clofibric acid, and3-(2,5-xylyloxy)-l-propyl, a component of gemfibrozil; or

[0076] Y is

[0077] wherein R is hydrogen or methyl, and in which NSAID means anaromatic, alkyl, or cycloalkyl moiety that may contain heteroatoms andthat are generally part of the family of non-steroidal anti-inflammatoryagents. Preferred examples include, but are not limited to4-(2-methyl-1-propyl)phenyl, 2-(2,6-dichloro-1-phenyl)aminophenyl,6′-methoxy-2′-naphthyl, and 6′-methoxy-2′-naphthylmethyl or

[0078] Y can be

[0079] where α and β are hydrogen or α and β form a bond, and where γ,δ, and ε, are independently hydrogen, hydroxy, fluoro, chloro, ormethyl; or

[0080] Y can be

[0081] Alternatively X can be an N-subsfituted2-methylaminoethoxycarbonyl or an N-substituted 2-methylaminoacetoxy,having the following formulas:

[0082] wherein Y is

[0083] n is 0 or 1; R₂ and R₃ are independently hydrogen or methyl; Z isN, O, or S; and R₁ is aryl, heteroaryl, alkyl or heteroalkyl. Preferrednon-limiting examples include compounds where R₁ is phenyl,4-fluorophenyl, 4-methoxyphenyl, 3-methyl-2-thiophenyl,5-methyl-2-thiophenyl, 5-methyl-3-isoxazolyl, 2-pyridyl, 4-pyridyl, or2-pyrazinyl, 2-hydroxybenzoyl, or 2,4-dihydroxybenzoyl; or

[0084] Y is

[0085] n is 0 or 1; m is 0 or 1; R₂ and R₃ are independently hydrogen ormethyl; Z is N, O, or S; and R₁ is aryl or heteroaryl, alkyl orheteroalkyl. Preferred non-limiting examples include compounds where R₁is phenyl, 4-fluorophenyl, 4-methoxyphenyl, 3-methyl-2-thiophenyl,5-methyl-2-thiophenyl, 5-methyl-3-isoxazolyl, 2-pyridyl, 4-pyridyl,2-pyrazinyl, 2-hydroxybenzoyl, or 2,4-dihydroxybenzoyl; or

[0086] Y is

[0087] wherein Hetero is an aromatic, cyclic, or alicyclic moiety thatcontains heteroatoms. In certain specific embodiments, these moietiesare part of the structure of the statin-family of lipid lowering agents.Preferred examples include, but are not limited to,2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1-(1H-pyrrol)yl,a component of atorvastatin, and1,2,3,7,8,8a-hexahydro-1-(2-methylbutanoyl)oxy-3,7-dimethyl-8-naphthalenyl,a component of lovastatin; or

[0088] Y is

[0089] wherein Fib is an aromatic, cyclic, or alicyclic moiety thatcontains heteroatoms. In some embodiments, these moieties are part ofthe fibrate-family of lipid lowering agents. Preferred examples include,but are not limited to 4-(4-chlorobenzoyl)phenoxy, a component offenofibric acid, 4-chlorophenoxy, a component of clofibric acid, and3-(2,5-xylyloxy)-1-propyl, a component of gemfibrozil; or

[0090] Y is

[0091] wherein R is hydrogen or methyl, and in which NSAID means anaromatic, alkyl, or cycloalkyl moiety that may contain heteroatoms andthat are generally part of the family of non-steroidal anti-inflammatoryagents. Preferred examples include, but are not limited to4-(2-methyl-1-propyl)phenyl, 2-(2,6-dichloro-1-phenyl)aminophenyl,6′-methoxy-2′-naphthyl, and 6′-methoxy-2′-naphthylmethyl; or

[0092] Y can be

[0093] where α and β are hydrogen or α and β form a bond, and where γ,δ, and ε, are independently hydrogen, hydroxy, fluoro, chloro, ormethyl; or

[0094] Y can be

[0095] Other embodiments provide compounds wherein X is

[0096] R₄ is hydrogen or methyl, and where R₅ is aryl or heteroaryl,alkyl or heteroalkyl. Preferred non-limiting examples include compoundswhere R₅ is phenyl, 4-fluorophenyl, 4-methoxyphenyl,3-methyl-2-thiophenyl, 5-methyl-2-thiophenyl, 5-methyl-3-isoxazolyl,2-pyridyl, 4-pyridyl, 2-pyrazinyl,(R)-6-hydroxy-2,5,7,8-tetramethyl-2-chromanyl,(S)-6-hydroxy-2,5,7,8-tetramethyl-2-chromanyl,(R)-5-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-3-benzofuranyl, or(S)-5-hydroxy-2,2,4, 6,7-pentamethyl-2,3-dihydro-3-benzo-furanyl.

[0097] X can also be

[0098] wherein R4 is hydrogen or methyl, and where R5 is aryl orheteroaryl, alkyl or heteroalkyl. Preferred non-limiting examplesinclude compounds where R5 is phenyl, 4-fluorophenyl, 4-methoxyphenyl,3-methyl-2-thiophenyl, 5-methyl-2-thiophenyl, 5-methyl-3-isoxazolyl,2-pyridyl, 4-pyridyl, 2-pyrazinyl,(R)-6-hydroxy-2,5,7,8-tetramethyl-2-chromanyl,(S)-6-hydroxy-2,5,7,8-tetramethyl-2-chromanyl,(R)-5-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-3-benzofuranyl, or(S)-5-hydroxy-2,2,4, 6,7-pentamethyl-2,3-dihydro-3-benzofuranyl.

[0099] In one embodiment, A is NH; B is sulfur (S); P and Q are a doublebond or hydrogen (H); E is hydrogen (H) and is attached to each of D₁through D₆; D₁ through D₆ are carbon (C); and X can be any of thestructures provided supra.

[0100] Modifications of the compounds disclosed herein can readily bemade by those skilled in the art. Thus, analogs, derivatives, and saltsof the exemplified compounds are within the scope of the subjectinvention. With a knowledge of the compounds of the subject invention,and their structures, skilled chemists can use known procedures tosynthesize these compounds from available substrates.

[0101] As used in this application, the terms “analogs” and“derivatives” refer to compounds which are substantially the same asanother compound but which may have been modified by, for example,adding additional side groups. The terms “analogs” and “derivatives” asused in this application also may refer to compounds which aresubstantially the same as another compound but which have atomic ormolecular substitutions at certain locations in the compound.

[0102] Analogs or derivatives of the exemplified compounds can bereadily prepared using commonly known, standard reactions. Thesestandard reactions include, but are not limited to, hydrogenation,methylation, acetylation, and acidification reactions. For example, newsalts within the scope of the invention can be made by adding mineralacids, e.g., HCl, H₂SO₄, etc., or strong organic acids, e.g., formic,oxalic, etc., in appropriate amounts to form the acid addition salt ofthe parent compound or its derivative. Also, synthesis type reactionsmay be used pursuant to known procedures to add or modify various groupsin the exemplified compounds to produce other compounds within the scopeof the invention.

[0103] The subject invention further provides methods of treatingdisorders, such as diabetes, atherosclerosis, hypercholesterolemia, andhyperlipidemia, comprising the administration of a therapeuticallyeffective amount of esterified thiazolidinedione analogs to anindividual in need of treatment. Thiazolidinedione based compoundsinclude troglitazone (for example, REZULIN), pioglitazone, androsiglitazone. Accordingly, the subject invention provides esterifiedthiazolidinedione analogs and pharmaceutical compositions of theseesterified compounds. The compounds and compositions according to theinvention can also be administered in conjunction with other therapeuticcompounds, therapeutic regimens, compositions, and agents suitable forthe treatment of disorders, such as diabetes, atherosclerosis,hypercholesterolemia, and hyperlipidemia. Thus, the invention includescombination therapies wherein the compounds and compositions of theinvention are used in conjunction with other therapeutic agents for thetreatment of disorders, such as diabetes, atherosclerosis,hypercholesterolemia, and hyperlipidemia.

[0104] The compounds of this invention have therapeutic propertiessimilar to those of the unmodified parent compounds. Accordingly, dosagerates and routes of administration of the disclosed compounds aresimilar to those already used in the art and known to the skilledartisan (see, for example, Physicians' Desk Reference, 54^(th) Ed.,Medical Economics Company, Montvale, N.J., 2000).

[0105] The compounds of the subject invention can be formulatedaccording to known methods for preparing pharmaceutically usefulcompositions. Formulations are described in detail in a number ofsources that are well known and readily available to those skilled inthe art. For example, Remington's Pharmaceutical Science by E. W. Martindescribes formulations that can be used in connection with the subjectinvention. In general, the compositions of the subject invention areformulated such that an effective amount of the bioactive compound(s) iscombined with a suitable carrier in order to facilitate effectiveadministration of the composition.

[0106] In accordance with the subject invention, pharmaceuticalcompositions are provided which comprise, as an active ingredient, aneffective amount of one or more of the compounds of the invention andone or more non-toxic, pharmaceutically acceptable carriers or diluents.Examples of such carriers for use in the invention include ethanol,dimethyl sulfoxide, glycerol, silica, alumina, starch, and equivalentcarriers and diluents. Additional therapeutic agents suitable for thetreatment of disorders such as diabetes, atherosclerosis,hypercholesterolemia, and hyper-lipidemia can also be incorporated intopharmaceutical agents according to the invention.

[0107] Further, acceptable carriers can be either solid or liquid. Solidform preparations include powders, tablets, pills, capsules, cachets,suppositories and dispersible granules. A solid carrier can be one ormore substances that may act as diluents, flavoring agents,solubilizers, lubricants, suspending agents, binders, preservatives,tablet disintegrating agents or encapsulating materials.

[0108] The disclosed pharmaceutical compositions may be subdivided intounit doses containing appropriate quantities of the active component.The unit dosage form can be a packaged preparation, such as packetedtablets, capsules, and powders in paper or plastic containers or invials or ampoules. Also, the unit dosage can be a liquid basedpreparation or formulated to be incorporated into solid food products,chewing gum, or lozenge.

[0109] Adverse drug-drug interactions (DDI), elevation of liver functiontest (LFT) values, and QT prolongation leading to torsades de pointes(TDP) are three major reasons why drug candidates fail to obtain FDAapproval. All these causes are, to some extent metabolism-based. A drugthat has two metabolic pathways, one oxidative and one non-oxidative,built into its structure is highly desirable in the pharmaceuticalindustry. An alternate, non-oxidative metabolic pathway provides thetreated subject with an alternative drug detoxification pathway (anescape route) when one of the oxidative metabolic pathways becomessaturated or non-functional. While a dual metabolic pathway is necessaryin order to provide an escape metabolic route, other features are neededto obtain drugs that are safe regarding DDI, TDP, and LFT elevations.

[0110] In addition to having two metabolic pathways, the drug shouldhave a rapid metabolic clearance (short metabolic half-life) so thatblood levels of unbound drug do not rise to dangerous levels in cases ofDDI at the protein level. Also, if the metabolic half-life of the drugis too long, then the CYP450 system again becomes the main eliminationpathway, thus defeating the original purpose of the design. In order toavoid high peak concentrations and rapidly declining blood levels whenadministered, such a drug should also be administered using a deliverysystem that produces constant and controllable blood levels over time.

[0111] The subject invention also provides therapeutically useful andeffective compounds and compositions for the treatment of diabetes and avariety of related disorders, such as hyperlipidemia, andatherosclerosis. Various classes of compounds, useful for the treatmentof diabetes and related disorders, that can be modified according to theconcepts outlined herein include compounds such as the glitazones,thiazolidinediones, and isoxazolidinediones

[0112] The compounds of this invention have one or more of the followingcharacteristics or properties:

[0113] 1. Compounds of the invention are metabolized both by CYP450 andby a non-oxidative metabolic enzyme or system of enzymes;

[0114] 2. Compounds of the invention have a short (up to four (4) hours)non-oxidative metabolic half-life;

[0115] 3. Oral bioavailability of the compounds is consistent with oraladministration using standard pharmaceutical oral formulations; however,the compounds, and compositions thereof, can also be administered usingany delivery system that produces constant and controllable blood levelsover time;

[0116] 4. Compounds according to the invention contain a hydrolysablebond that can be cleaved non-oxidatively by hydrolytic enzymes;

[0117] 5. Compounds of the invention can be made using standardtechniques of small-scale and large-scale chemical synthesis;

[0118] 6. The primary metabolite(s) of compound(s) of this inventionresult(s) from the non-oxidative metabolism of the compound(s);

[0119] 7. The primary metabolite(s), regardless of the solubilityproperties of the parent drug, is, or are, soluble in water atphysiological pH and have, as compared to the parent compound, asignificantly reduced pharmacological activity;

[0120] 8. The primary metabolite(s), regardless of theelectrophysiological properties of the parent drug, has, or have,negligible inhibitory activity at the IKR (HERG) channel at normaltherapeutic concentration of the parent drug in plasma (e.g., theconcentration of the metabolite must be at least five times higher thanthe normal therapeutic concentration of the parent compound beforeactivity at the IKR channel is observed);

[0121] 9. Compounds of the invention, as well as the metabolitesthereof, do not cause metabolic DDI when co-administered with otherdrugs;

[0122] 10. Compounds of the invention, as well as metabolites thereof,do not elevate LFT values when administered alone.

[0123] In some embodiments, the subject invention provides compoundshave any two of the above-identified characteristics or properties.Other embodiments provide for compounds having at least any three of theabove-identified properties or characteristics. In another embodiment,the compounds, and compositions thereof, have any combination of atleast four of the above-identified characteristics or properties.Another embodiment provides compounds have any combination of five to 10of the above-identified characteristics or properties. In a preferredembodiment the compounds of the invention have all ten characteristicsor properties.

[0124] In various embodiments, the primary metabolite(s) of theinventive compounds, regardless of the electrophysiological propertiesof the parent drug, has, or have, negligible inhibitory activity at theIKR (HERG) channel at normal therapeutic concentrations of the drug inplasma. In other words, the concentration of the metabolite must be atleast five times higher than the normal therapeutic concentration of theparent compound before activity at the IKR channel is observed.Preferably, the concentration of the metabolite must be at least tentimes higher than the normal therapeutic concentration of the parentcompound before activity at the IK_(R) channel is observed.

[0125] Compounds according to the invention are, primarily, metabolizedby endogenous hydrolytic enzymes via hydrolysable bonds engineered intotheir structures. The primary metabolites resulting from this metabolicpathway are water soluble and do not have, or show a reduced incidenceof, DDI when administered with other medications (drugs). Non-limitingexamples of hydrolysable bonds that can be incorporated into compoundsaccording to the invention include amide, ester, carbonate, phosphate,sulfate, urea, urethane, glycoside, or other bonds that can be cleavedby hydrolases.

[0126] Additional modifications of the compounds disclosed herein canreadily be made by those skilled in the art. Thus, analogs, derivatives,and salts of the exemplified compounds are within the scope of thesubject invention. With a knowledge of the compounds of the subjectinvention skilled chemists can use known procedures to synthesize thesecompounds from available substrates. As used in this application, theterms “analogs” and “derivatives” refer to compounds which aresubstantially the same as another compound but which may have beenmodified by, for example, adding additional side groups. The terms“analogs” and “derivatives” as used in this application also may referto compounds which are substantially the same as another compound butwhich have atomic or molecular substitutions at certain locations in thecompound.

[0127] The subject invention further provides novel drugs that are dosedvia drug delivery systems that achieve slow release of the drug over anextended period of time. These delivery systems maintain constant druglevels in the target tissue or cells. Such drug delivery systems havebeen described, for example, in Remington: The Science and Practice ofPharmacy, 19^(th) Ed., Mack Publishing Co., Easton, Pa., 1995, pp1660-1675, which is hereby incorporated by reference in its entirety.Drug delivery systems can take the form of oral dosage forms, parenteraldosage forms, transdermal systems, and targeted delivery systems.

[0128] Oral sustained-release dosage forms are commonly based on systemsin which the release rate of drug is determined by its diffusion througha water-insoluble polymer. There are basically two types of diffusiondevices, namely reservoir devices, in which the drug core is surroundedby a polymeric membrane, and matrix devices, in which dissolved ordispersed drug is distributed uniformly in an inert, polymeric matrix.In actual practice, however, many diffusion devices also rely on somedegree of dissolution in order to govern the release rate.

[0129] Dissolution systems are based on the fact that drugs with slowdissolution rates inherently produce sustained blood levels. Therefore,it is possible to prepare sustained-release formulations by decreasingthe dissolution rate of highly water-soluble drugs. This can be carriedout by preparing an appropriate salt or other derivative, by coating thedrug with a slowly soluble material, or by incorporating it into atablet with a slowly soluble carrier.

[0130] In actual practice, most of the dissolution systems fall into twocategories: encapsulated dissolution systems and matrix dissolutionsystems. Encapsulated dissolution systems can be prepared either bycoating particles or granules of drug with varying thicknesses of slowlysoluble polymers or by micro-encapsulation, which can be accomplished byusing phase separation, interfacial polymerization, heat fusion, or thesolvent evaporation method. The coating materials may be selected from awide variety of natural and synthetic polymers, depending on the drug tobe coated and the release characteristics desired. Matrix dissolutiondevices are prepared by compressing the drug with a slowly solublepolymer carrier into a tablet form.

[0131] In osmotic pressure-controlled drug-delivery systems, osmoticpressure is utilized as the driving force to generate a constant releaseof drug. Additionally, ion-exchange resins can be used for controllingthe rate of release of a drug, which is bound to the resin by prolongedcontact of the resin with the drug solution. Drug release from thiscomplex is dependent on the ionic environment within thegastrointestinal tract and the properties of the resin.

[0132] Parenteral sustained-release dosage forms most commonly includeintramuscular injections, implants for subcutaneous tissues and variousbody cavities, and transdermal devices. Intramuscular injections cantake the form of aqueous solutions of the drug and a thickening agentwhich increases the viscosity of the medium, resulting in decreasedmolecular diffusion and localization of the injected volume. In thismanner, the absorptive area is reduced and the rate of drug release iscontrolled. Alternatively, drugs can be complexed either with smallmolecules such as caffeine or procaine or with macromolecules, e.g.,biopolymers such as antibodies and proteins or synthetic polymers, suchas methylcellulose or polyvinylpyrrolidone. In the latter case, theseformulations frequently take on the form of aqueous suspensions. Drugswhich are appreciably lipophilic can be formulated as oil solutions oroil suspensions in which the release rate of the drug is determined bypartitioning of the drug into the surrounding aqueous medium. Theduration of action obtained from oil suspensions is generally longerthan that from oil solutions, because the suspended drug particles mustfirst dissolve in the oil phase before partitioning into the aqueousmedium. Water-oil (W/O) emulsions, in which water droplets containingthe drug are dispersed uniformly within an external oil phase, can alsobe used for sustained release. Similar results can be obtained from O/W(reverse) and multiple emulsions.

[0133] Implantable devices based on biocompatible polymers allow forboth a high degree of control of the duration of drug activity andprecision of dosing. In these devices, drug release can be controlledeither by diffusion or by activation. In diffusion-type implants, thedrug is encapsulated within a compartment that is enclosed by arate-limiting polymeric membrane. The drug reservoir may contain eitherdrug particles or a dispersion (or a solution) of solid drug in a liquidor a solid-type dispersing medium. The polymeric membrane may befabricated from a homogeneous or a heterogeneous non-porous polymericmaterial or a microporous or semi-permeable membrane. The encapsulationof the drug reservoir inside the polymeric membrane may be accomplishedby molding, encapsulation, microencapsulation or other techniques.Alternatively, the drug reservoir is formed by the homogeneousdispersion of drug particles throughout a lipophilic or hydrophilicpolymer matrix. The dispersion of the drug particles in the polymermatrix may be accomplished by blending the drug with a viscous liquidpolymer or a semi-solid polymer at room temperature, followed bycrosslinking of the polymer, or by mixing of the drug particles with amelted polymer at an elevated temperature. It can also be fabricated bydissolving the drug particles and/or the polymer in an organic solventfollowed by mixing and evaporation of the solvent in a mold at anelevated temperature or under vacuum.

[0134] In microreservoir dissolution-controlled drug delivery, the drugreservoir, which is a suspension of drug particles in an aqueoussolution of a water-miscible polymer, forms a homogeneous dispersion ofa multitude of discrete, unleachable, microscopic drug reservoirs in apolymer matrix. The microdispersion may be generated by using ahigh-energy dispersing technique. Release of the drug from this type ofdrug delivery device follows either an interfacial partition or a matrixdiffusion-controlled process.

[0135] In activation-type implants, the drug is released from thesemi-permeable reservoir in solution form at a controlled rate under anosmotic pressure gradient. Implantable drug-delivery devices can also beactivated by vapor pressure, magnetic forces, ultrasound, or hydrolysis.

[0136] Transdermal systems for the controlled systemic delivery of drugsare based on several technologies. In membrane-moderated systems, thedrug reservoir is totally encapsulated in a shallow compartment moldedfrom a drug-impermeable backing and a rate-controlling microporous ornon-porous polymeric membrane through which the drug molecules arereleased. On the external surface of the membrane, a thin layer ofdrug-compatible, hypoallergenic adhesive polymer may be applied toachieve an intimate contact of the transdermal system with the skin. Therate of drug release from this type of delivery system can be tailoredby varying the polymer composition, permeability coefficient orthickness of the rate-limiting membrane and adhesive.

[0137] In adhesive diffusion-controlled systems, the drug reservoir isformulated by directly dispersing the drug in an adhesive polymer andthen spreading the medicated adhesive, by solvent casting, onto a flatsheet of drug-impermeable backing membrane to form a thin drug reservoirlayer. On top of the drug-reservoir layer, layers of non-medicated, ratecontrolling adhesive polymer of constant thickness are applied toproduce an adhesive diffusion-controlled drug-delivery system.

[0138] In matrix dispersion systems, the drug reservoir is formed byhomogeneously dispersing the drug in a hydrophilic or lipophilic polymermatrix. The medicated polymer is then molded into a disc with a definedsurface area and controlled thickness. The disc is then glued to anocclusive baseplate in a compartment fabricated from a drug-impermeablebacking. The adhesive polymer is spread along the circumference to forma strip of adhesive rim around the medicated disc. In microreservoirsystems, the drug reservoir is formed by first suspending the drugparticles in an aqueous solution of a water-soluble polymer and thendispersing homogeneously, in a lipophilic polymer, by high-shearmechanical forces to form a large number of unleachable, microscopicspheres of drug reservoirs. This thermodynamically unstable system isstabilized by crosslinking the polymer in situ, which produces amedicated polymer disk with a constant surface area and a fixedthickness.

[0139] Targeted delivery systems include, but are not limited to,colloidal systems such as nanoparticles, microcapsules, nanocapsules,macromolecular complexes, polymeric beads, microspheres, and liposomes.Targeted delivery systems can also include resealed erythrocytes andother immunologically-based systems. The latter may includedrug/antibody complexes, antibody-targeted enzymatically-activatedprodrug systems, and drugs linked covalently to antibodies.

[0140] The invention also provides methods of producing these compounds.

[0141] It is another aspect of this invention to provide protocols bywhich these conditions can be tested. These protocols include in vitroand in vivo tests that have been designed to: 1) ensure that the novelcompound is metabolized both by CYP450 and by hydrolytic enzymes; 2)that the non-oxidative half-life of the parent drug is no more than acertain value when compared to an internal standard (in preferredembodiments, less than about four hours); 3) that the primary metaboliteof the parent drug is the result of non-oxidative metabolism; 4) thatthe primary metabolite of the parent drug (regardless of the solubilityproperties of the parent drug) is water soluble; 5) that the primarymetabolite of the parent drug (regardless of the electrophysiologicalproperties of the parent drug) has negligible inhibitory propertiestoward IKR channel at concentrations similar to therapeuticconcentration of the parent drug; 6) that the novel compound (regardlessof its properties) does not cause metabolic DDI when co-administeredwith other drugs; and 7) that the novel compound does not cause hepatictoxicity in primary human hepatocytes.

[0142] The subject invention provides materials and methods for thetreatment of non-insulin dependent diabetes mellitus (NIDDM),hyperlipidemia, hypercholesterolemia, and atherosclerosis.Advantageously, the therapeutic compounds of the subject invention arestable in storage but have a shorter half-life in the physiologicalenvironment than other drugs which are available for treatment ofdiabetes; therefore, the compounds of the subject invention can be usedwith a lower incidence of side effects and toxicity, especially inpatients having elevated liver function or compromised liver function.

[0143] In another embodiment of the subject invention, therapeuticcompounds are provided which are useful in the treatment of diabetes,hyperlipidemia, hypercholesterolemia, and atherosclerosis and whichcontain an ester group which is acted upon by esterases thereby breakingdown the compound and facilitating its efficient removal from thetreated individual. In a preferred embodiment, the therapeutic compoundsare metabolized by non-oxidative systems and are exemplified by thecompound of Formula IB.

[0144] For compounds of Formula IB:

[0145] A, B, and F may be the same or different and are CH₂, CO, N, NO,NH, SO₀₋₂, O;

[0146] D₁-D₆ can be the same or different and are CH, N, S, or O;

[0147] E can be a substituent attached to one or more of the atomslocated at D₁-D₆;

[0148] P and Q can be a double bond; or

[0149] P, Q, and E can be the same or different and are a moietyselected from the group consisting of H, C₁₋₁₀ alkyl, substituted alkylgroups, substituted or unsubstituted carboxylic acids, substituted orunsubstituted carboxylic esters, halogen, carboxyl, hydroxyl, phosphate,phosphonate, aryl, CN, OH, COOH, NO₂, NH₂, SO₂₋₄, C₁₋₂₀ heteroalkyl,C₂₋₂₀ alkenyl, alkynyl, akynyl-aryl, alkynyl-heteroaryl, aryl, C₁₋₂₀alkyl-aryl, C₂₋₂₀ alkenyl-aryl, heteroaryl, C₁₋₂₀ alkyl-heteroaryl,C₂₋₂₀ alkenyl-heteroaryl, cycloalkyl, heterocycloalkyl, C₁₋₂₀alkyl-heteroycloalkyl, and C₁₋₂₀ alkyl-cycloalkyl, any of which may be,optionally, substituted with a moiety selected from the group consistingof C₁₋₆ alkyl, halogen, OH, NH₂, CN, NO₂, COOH, or SO₂₋₄. Exemplaryheterocyclic groups include, but not limited to, morpholine, triazole,imidazole, pyrrolidine, piperidine, piperazine, pyrrole,dihydropyridine, aziridine, thiazolidine, thiazoline, thiadiazolidine orthiadiazoline.

[0150] Substituted carboxylic acids, substituted carboxylic esters, andsubstituted alkyl groups can be substituted at any available positionwith a moiety selected from the group consisting of C₁₋₁₀ alkyl,halogen, CN, OH, COOH, NO₂, NH₂, SO₂₋₄, C₁₋₂₀ heteroalkyl, C₂₋₂₀alkenyl, alkynyl, akynyl-aryl, alkynyl-heteroaryl, aryl, C₁₋₂₀alkyl-aryl, C₂₋₂₀ alkenyl-aryl, heteroaryl, C₁₋₂₀ alkyl-heteroaryl,C₂₋₂₀ alkenyl-heteroaryl, cycloalkyl, heterocycloalkyl, C₁₋₂₀alkyl-heteroycloalkyl, and C₁₋₂₀ alkyl-cycloalkyl, any of which may be,optionally, substituted with a moiety selected from the group consistingof C₁₋₆ alkyl, halogen, OH, NH₂, CN, NO₂, COOH, or SO₂₋₄. Exemplaryheterocyclic groups include, but are not limited to, morpholine,triazole, imidazole, pyrrolidine, piperidine, piperazine, pyrrole,dihydropyridine, aziridine, thiazolidine, thiazoline, thiadiazolidine,and thiadiazoline.

[0151] X is —OH, —COOH, or a substituted carboxylic group having thecarboxyl moiety OOC— or COO— directly attached to the phenyl ring of thecompound of Formula IB. The carboxylic acid group can be substitutedwith a moiety selected from the group consisting of alkyloxycarbonyl,alkylcarbonyloxy, aryloxycarbonyl, arylcarbonyloxy,heteroalkyloxycarbonyl, heteroalkylcarbonyloxy, heteroaryl-oxycarbonyl,and heteroarylcarbonyloxy each of which is, optionally, substituted withC₁₋₁₀ alkyl, CN, COOH, NO₂, NH₂, SO₂₋₄, C₁₋₂₀ heteroalkyl, C₂₋₂₀alkenyl, alkynyl, akynyl-aryl, alkynyl-heteroaryl, aryl, C₁₋₂₀alkyl-aryl, C₂₋₂₀ alkenyl-aryl, heteroaryl, C₁₋₂₀ alkyl-heteroaryl,C₂₋₂₀ alkenyl-heteroaryl, cycloalkyl, heterocycloalkyl, C₁₋₂₀alkyl-heteroycloalkyl, and C₁₋₂₀ alkyl-cycloalkyl, any of which may be,optionally, substituted with a moiety selected from the group consistingof C₁₋₆ alkyl, halogen, OH, NH₂, CN, NO₂, COOH, or SO₂₋₄. In otherembodiments, the substituted carboxylic group can be substituted with amoiety selected from the group consisting of C₁₋₁₀ alkyl, CN, COOH, NO₂,NH₂, SO₂₋₄, C₁₋₂₀ heteroalkyl, C₂₋₂₀ alkenyl, alkynyl, akynyl-aryl,alkynyl-heteroaryl, aryl, C₁₋₂₀ alkyl-aryl, C₂₋₂₀ alkenyl-aryl,heteroaryl, C₁₋₂₀ alkyl-heteroaryl, C₂₋₂₀ alkenyl-heteroaryl,cycloalkyl, heterocycloalkyl, C₁₋₂₀ alkyl-heteroycloalkyl, and C₁₋₂₀alkyl-cycloalkyl, any of which may be, optionally, substituted with amoiety selected from the group consisting of C₁₋₆ alkyl, halogen, OH,NH₂, CN, NO₂, COOH, or SO₂₋₄. Exemplary heterocyclic groups include, butare not limited to, morpholine, triazole, imidazole, pyrrolidine,piperidine, piperazine, pyrrole, dihydropyridine, aziridine,thiazolidine, thiazoline, thiadiazolidine, and thiadiazoline.

[0152] In one exemplary embodiment, compounds of the invention of FIG.1B have the following moieties: A is NH; F is O; B is C═O; P and Q are adouble bond or H; D₁-D₆ are C (carbon), E is hydrogen; X is selectedfrom the group consisting of:

[0153] A further aspect of the subject invention provides procedures forsynthesizing the therapeutic compounds of interest. An exemplarysynthesis scheme is shown in FIGS. 23-25. In step 1, β-benzyl aspartateis suspended in triethylamine and acetic anhydride is added slowly at 0°C. with stirring. A catalytic amount of DMAP is then added underice-cooling. The mixture is stirred overnight at room temperature andthen ice-water is added. The pH is brought up to 9.0 with KOH solutionand the product is extracted with ethyl acetate, dried, andconcentrated.

[0154] In step 2, the acetamide group and the benzyl ester are cleavedwith 6N HCI at reflux for 2 hours. The resulting amino acid is thenisolated, dried, and then dissolved in a solution of thionyl chloride inmethanol. After refluxing for 4 hours, the resulting methyl ester 3 isobtained.

[0155] In step 3, the amine compound 3 is suspended in dichloromethaneand benzoyl chloride and triethylamine are added under ice-cooling.After stirring for 5 hours at room temperature, the product is washedwith sodium bicarbonate solution, dried, and evaporated to give thebenzamide 4.

[0156] In step 4, the oxazole 5 is formed by dissolving compound 4 inanhydrous ethyl acetate and treating with a catalytic amount of sulfuricacid for 3 hours at 90° C. The product is isolated as usual.

[0157] In step 5, the carboxylic acid 6 is obtained by treating 5 with 1equivalent amount of lithium hydroxide in methanol/water.

[0158] Steps 6 and 7 can be combined in a one-pot reaction as follows:Acetylacetone 7 (1.5mol) is dissolved in 450 ml of glacial acetic acidand the solution is cooled to 5° C. Sodium nitrite (1.5 mol in 150 ml ofwater) is added slowly so that the temperature stays between 5 and 7° C.Keep stirring for 4 hours at room temperature then add zinc powder (3mol) portionwise under ice-cooling. Keep stirring at room temperatureuntil the reaction is over and then collect the product 9 by filtration.Dry thoroughly.

[0159] Steps 8 and 9 proceed as described before. The amine 9 reactswith benzoyl chloride in dichloromethane in the presence oftriethylamine in order to give the benzamide 10. The oxazole 11 is thenobtained by cyclization with a catalytic amount of sulfuric acid atreflux in anhydrous ethyl acetate.

[0160] In step 10, treating the ketone 11 with 1 equivalent of methylmagnesium iodide in tetrahydrofuran at −40° C. gives the tertiaryalcohol 12.

[0161] In step 11, the ketone 11 is reduced to the secondary alcohol 13with sodium borohydride in methanol.

[0162] In step 12, p-methoxybenzaldehyde 14 reacts with dimethylmalonate in methanol with a catalytic amount of piperidinium benzoate,giving the benzylidene product 15.

[0163] In step 13, the benzylidene 15 is hydrolyzed inmethanol/NaOH/water and then is acidified with dilute HCl to give thediacid. The diacid in turn reacts with thionyl chloride to give the acidchloride 16.

[0164] In step 14, the acid chloride 16 is dissolved in dichloromethaneand triethylamine. Hydroxylamine hydrochloride is added underice-cooling, giving the isoxazolidine 17.

[0165] In step 15, the methoxy-group in compound 17 is cleaved readilyby boron tribromide, yielding the phenolic compound 18.

[0166] In step 16, the benzylidene compound 15 is reduced by magnesiumpowder in ethanol, giving dimethyl 4-methoxybenzylmalonate 19.

[0167] In steps 17, 18, and 19, compound 19 undergoes a similar sequenceof reactions as in steps 13, 14, and 15, i.e., hydrolysis withNaOH/methanol/water and subsequent reaction with thionyl chloride togive the acid chloride 20. Compound 20 in turn reacts with hydroxylaminehydrochloride in dichloromethane and triethylamine to give 21. Finally,cleavage of the ether function with boron tribromide yields the phenoliccompound 22.

[0168] In step 21, p-carboxybenzaldehyde 24 reacts with2,4-isoxalolidinedione 25 (made from malonyl chloride and hydroxylamine,step 20) in THF in the presence of piperidinium benzoate to give thebenzylidene 26.

[0169] In step 22, compound 26 is reduced with magnesium powder inethanol to give 3-(4-carboxybenzyl)-isoxazolidine-2,4-dione 27.

[0170] In step 23, the carboxylic acid 26 reacts with the secondaryalcohol 13 in dichloromethane in the presence of 1 equivalent amount ofdicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP),giving the ester 28.

[0171] The same reaction takes place in step 24 between compounds 27 and13, giving the ester 29.

[0172] Compounds 28 and 29 are among the group of preferredisoxazolidinedione analogs that have therapeutic properties againstNIDDM and related diseases in mammals.

[0173] In step 25, the phenolic compound 18 reacts with the carboxylicacid 6 in dichloromethane in the presence of 1 equivalent amount ofdicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP),giving the ester 30.

[0174] The same reaction takes place in step 26 between compounds 22 and6, giving the ester 31.

[0175] Compounds 30 and 31 are among the group of preferredisoxazolidinedione analogs that have therapeutic properties againstNIDDM and related diseases in mammals.

[0176] Ethyl acetoacetate 32 undergoes the same chemical treatment insteps 27 to 29 as acetylacetone 7 in steps 6 to 9 (FIG. 3). Thus,compound 32 in glacial acetic acid reacts with sodium nitrite, and theresulting oxime intermediate is not isolated but is reduced with zincpowder in acetic acid to give the amine 33. The amine is then coupledwith benzoyl chloride in dichloromethane in the presence oftriethylamine.

[0177] The resulting benzamide 34 is then cyclized with a catalyticamount of sulfuric acid in refluxing ethyl acetate, giving thesubstituted oxazole 35.

[0178] In step 30, the ethyl carboxylate function of compound 35 isreduced with lithium aluminum hydride in THF to give the primary alcohol36 (an analog of compounds 12 and 13).

[0179] In step 31, the ethyl carboxylate function of compound 35 ishydrolyzed in 6N HCl to give the carboxylic acid 37 (an analog ofcompound 6.

[0180] Compounds 1 through 4 (of Table I) can be conveniently preparedby the Knoevenagel reaction between an aldehyde andthiazolidine-2,4-dione, using for example sodium acetate in aceticanhydride, or piperidine and benzoic acid in methylene chloride as areaction medium. This is illustrated in FIG. 2 and FIG. 3.Alternatively, compound 1 can be prepared by the method described inFIG. 4. In this reaction scheme, para-anisidine undergoes a diazotationreaction with sodium nitrite and hydrochloric acid. The diazoniumchloride salt undergoing, in turn, a radicalar reaction with methylacrylate and then a cyclization reaction with thiourea, the product ofwhich is hydrolyzed to the thiazolidinedione molecule.

[0181] The compounds described in Table I (compounds 5 to 32) can all bemade via an esterification reaction between 1 or 2 and an appropriatelysubstituted carboxylic acid, or between 3 or 4 and an appropriatelysubstituted alcohol. The esterification reaction can be facilitated bythe presence of a catalyst in the reaction medium, such as a smallamount of concentrated sulfuric acid for example. Preferably, especiallyif the alpha-position to the carbonyl is an asymmetric center, anactivated functional derivative of the carboxylic acid is made. Numerousfunctional derivatives of carboxylic acids used in esterificationreactions have been described in the scientific literature. The mostcommonly used activated functional derivatives are acyl chlorides,anhydrides and mixed anhydrides, and activated esters. In one aspect ofthis invention dicyclohexyl carbodiimide (DCC) was used as an activatingagent (FIG. 5).

[0182] Compounds 33 to 104 are functionalized 5-methyloxazole andfunctionalized 5-methylthiazole derivatives. They all have variousfunctional groups attached to the 2-position (R₁ in Tables II to V), andat the 4-position, which is the enzymatically labile link with thethiazolidine portion of the molecule. The enzymatically labile link iseither an ester (COO—) or a reverse ester (OOC—) and can be substitutedwith 0, 1, or 2 methyl groups at the alpha-position from the oxazole orthiazole ring (R₂ and R₃ in Tables II to V).

[0183] The synthesis of compounds 33 to 104 is described in generalterms in FIGS. 7-10. FIG. 6 describes the synthesis of the4-oxazoleacetic acid and the 4-oxazoleethanol moiety starting fromaspartic acid derivatives in which R₂ and R₃ are methyl or hydrogen. Ina typical example, γ-benzyl aspartate is acetylated and thendecarboxylated to benzyl 3-acetamido-4-oxovalerate using aceticanhydride as an acetylating agent followed by potassium hydroxide inorder to obtain the decarboxylated product. This in turn is transformedinto methyl 3-amino-4-oxovalerate using standard hydrolytic andesterification procedures, for example refluxing in dilute hydrochloricacid followed by reaction in thionyl chloride and methanol. The R₁ groupis then introduced by acylating the 3-amino group using the appropriateacyl or aroyl chloride. There is almost no limitation to the nature ofthe R₁ group being introduced at this stage, as shown in Tables II to Vwhere various R₁ groups are described. Cyclization to an oxazole ring isthen effected using sulfuric acid as a catalyst in ethyl acetate as asolvent. At this stage, ester hydrolysis using lithium hydroxide inmethanol gives the desired 4-oxazoleacetic acid derivatives, whereasreduction of the ester with lithium aluminum hydride or reduction of theacid using diborane gives the 4-oxazoleethanol analogs.

[0184]FIG. 7 describes the synthesis of the 4-oxazolecarboxylic acid and4-oxazolemethanol groups. The synthesis starts from ethyl acetoacetatein which a 2-amino-group is introduced via oxime formation followed byreduction with zinc powder. The synthesis then proceeds as before, wherethe R₁ group is introduced by acylating the amino group, followed bycyclization with sulfuric acid in ethyl acetate, and finally estercleavage or reduction to the alcohol.

[0185]FIG. 8 shows how steric hindrance can be introduced under the formof methyl groups on the 4-methanol moiety. Starting frompentane-2,4-dione, following the same synthetic sequence as in FIG. 7leads to the 4-acetyloxazole compounds which can be reduced by sodiumborohydride to the 4-(1-ethyl)oxazole. Alternatively, the compounds canbe transformed by methylmagnesium iodide into the tertiary alcoholanalogs. In another embodiment, condensation of a thioamide with methyl4-bromo-3-oxopentanoate gives methyl 4-thiazoleacetate, as described inFIG. 9. Ester cleavage with lithium hydroxide or reduction with lithiumaluminum hydride gives the corresponding acid or the alcohol,respectively.

[0186] Compounds 105 to 224 in Tables VI to XVII all have an amino acidor an amino alcohol as part of their structure. Their synthesis isdescribed in FIGS. 10 to 18. Any amino acid can be used in the synthesisof compounds according to this aspect of the invention. In certainembodiments, the amino acid group can be either proline or N-methylglycine and the amino alcohol group is their alcohol equivalent, i.e.,prolinol or N-methyl glycinol, respectively. As shown in FIGS. 10 to 13,the reaction of an alkyl chloride or a 2-heteroaryl chloride withproline, prolinol, N-methyl glycine, or N-methyl glycinol, in THF andtriethylamine gives the corresponding N-alkyl or N-heteroaryl adduct,respectively. When these adducts are carboxylic acids, such as in FIGS.10 and 12, they react with 5-(4-hydroxybenzyl)thiazolidine-2,4-dione inthe presence of DCC and DMAP to give compounds 105-108, 111, 112,125-128, 131, 132, 185-188, 191, 192. Carboxylic acid adducts react with5-(4-hydroxybenzylidene)thiazolidine-2,4-dione in the presence of DCCand DMAP to give compounds 115-118, 121, 122, 135-138, 141, 142,195-198, 201, 202. When these adducts are alcohols, such as in FIGS. 11and 13, they react with 5-(4-carboxybenzyl)thiazolidine-2,4-dione in thepresence of DCC and DMAP to give compounds 145-148, 151, 152, 165-168,171, 172, 205-208, 211, 212. Alcohol adducts react with5-(4-carboxybenzylidene)thiazolidine-2,4-dione in the presence of DCCand DMAP to give compounds 155-158, 161, 162, 175-178, 181, 182,215-218, 221, 222.

[0187] Alternatively, the amino acid or amino alcohol group can belinked to another group via an amide function, such as described inFIGS. 14 to 17. The synthesis of such compounds is straightforward. Whenthe compounds contain an amino acid, as in FIGS. 14 and 16, thesynthetic sequence is an amide bond formation, ester deprotection, andester formation.

[0188] As an illustrative example, (R)-Trolox® is combined withL-proline methyl ester, in the presence of DCC and DMAP in methylenechloride to form an amide intermediate. The methyl ester of the prolinegroup is then cleaved with lithium hydroxide in methanol, and theresulting carboxylic acid is combined with5-(4-hydroxybenzyl)thiazolidine-2,4-dione in DCC/DMAP/methylene chlorideto give compound 109. The (S)-isomer, compound 110, is made in a similarway. The same kind of synthetic scheme leads to compounds 113, 114, 119,120, 123, 124, 129, 130, 133, 134, 139, 140, 143, 144, 189, 190, 193,194, 199, 200, 203, and 204.

[0189] When the compounds contain an amino alcohol, as in FIGS. 15 and17, the synthetic sequence is an amide bond formation, followed by anester bond formation. As an illustrative example, (R)-Trolox® iscombined with L-prolinol in the presence of DCC and DMAP in methylenechloride to form an amide intermediate. The resulting amide is combinedwith 5-(4-carboxybenzyl)thiazolidine-2,4-dione in DCC/DMAP/methylenechloride to give compound 149. The (S)-isomer, compound 150, is made ina similar way. The same kind of synthetic scheme leads to compounds 153,154, 159, 160, 163, 164, 169, 170, 173, 174, 179, 180, 183, 184, 209,210, 213, 214, 219, 220, 223, and 224.

[0190] Compounds 225 to 242 (Table XVIII) are oxazoline-4-carboxylicacid types of compounds. Their synthesis (FIG. 18) starts from serine(R₅═H) or from threonine (R₅═CH₃) benzyl ester. The ester is coupledwith an alkyl or an arylcarboxylic acid using for example EDC as acoupling agent. The serine or threonine group then cyclizes into anoxazoline upon treatment with thionyl chloride. Coupling with5-(4-hydroxybenzyl)thiazolidine-2,4-dione using DCC/DMAP/methylenechloride gives compounds 225 to 242.

[0191] Compounds 243 to 248 (Table XIX) are thiazolidinedione moleculeswhere X is a group containing a substituted 2-methyl-2-propionylresidue. Examples include the 2-methyl-2-(4-chlorophenoxy)propionylmoiety (clofibryl moiety), the2-methyl-2-[4-(4-chlorobenzoyl)phenoxy]propionyl moiety (fenofibrylmoiety), and 2,2-dimethyl-5-(2,5-xylyloxy)valeryl moiety (gemfibrozilylmoiety).

[0192] Compounds 249 to 252 (Table XX) are thiazolidinedione moleculeswhere X is a group containing a substituted (R,R)-3,5-dihydroxyheptanoylresidue. Examples include the (βR,δR)-2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenyl-amino)carbonyl]1H-pyrrole-1-(β,δ,dihydroxy)heptanoylgroup (atorvastatin), and the 1,2,3,7,8,8a-hexahydro- 1-(2-methylbutanoyl)oxy-3,7-dimethylnaphthalenyl-8-[(3R,5R)-7-heptan]oylgroup (lovastatin). The synthesis of these compounds proceeds as in theexamples of Table I, (i.e., by a simple esterification procedure betweenthe lipid-lowering agent and compound 1 or compound 2).

[0193] Compounds 253 to 260 (Table XXI) are thiazolidinedione moleculeswhere X is a group containing an arylacetic acid residue, such as inmolecules that have non-steroidal anti-inflammatory properties. In theseexamples, the X group is an ibuprofen, ibufenac, naproxen, diclofenac,or nabumetone residue. The synthesis of these compounds is a simpleester formation reaction between the X group and compound 1 (P and Q arehydrogen) or compound 2 (P and Q form a bond).

[0194] Compounds 261 to 268 (Table XXII) are thiazolidinedione moleculeswhere X is a group containing a cortienic acid residue, such as inmolecules that have glucocorticoid anti-inflammatory properties. Inthese examples, the X group is a cortienic acid, 1,2-dihydrocortienicacid, 6α, 9α-difluoro-1,2-dihydrocortienic acid, and a9α-fluoro-16α-methyl-1,2-dihydrocortienic acid residue. The synthesis ofthese compounds is a simple ester formation reaction between the X groupand compound 1 (P and Q are hydrogen) or compound 2 (P and Q form abond). Cortienic acid, one of the many metabolites of hydrocortisone inman, can be synthetized from hydrocortisone by oxidation with sodiumperiodate. The substituted cortienic acid analogs can be made in anidentical manner from the corresponding substituted glucocorticoids.This oxidation procedure is described in detail in [Druzgala P.: NovelSoft Anti-inflammatory Glucocorticoids for Topical Application. Ph.D.Dissertation (1985), University of Florida, Gainesville, Fla., herebyincorporated by reference in its entirety].

[0195] Representative compounds were chosen and evaluated for activityon serum glucose and insulin levels in non-insulin dependent diabeticmellitus (NIDDM) KK-A^(y) male mice. Post-treatment data for each groupwere transferred to a percentage of pretreatment values and unpairedStudent's t test was used for comparison between vehicle and testsubstance treated groups. Results show a significant reduction of bothserum glucose and serum insulin relative to the vehicle control group.Reduction in serum glucose and serum insulin levels were comparable tothe reduction observed in the troglitazone-treated animals. The resultsare presented in Table XXI and in FIGS. 19 and 20.

EXAMPLES Example 1

[0196] To (S)-2-pyrrolidinemethanol (3.96g) in THF (30ml) is added2-chlorobenzoxazole (5.90 g) also in THF (80 ml) and then, dropwise,triethylamine (3.96 g). Stir at 50° C. for 4 hours. Cool to roomtemperature and filter out the solid. Evaporate the solvent and dissolvethe crude product in 5 ml of methylene chloride. Pass through a silicaplug (50 g) in a fritted filter funnel, and elute withmethanol/methylene chloride (10:90), applying suction until the producthas been collected. The yield of(S)-1-(2-benzoxazolyl)-2-hydroxymethylpyrrolidine is 8.2 g.

Example 2

[0197] To (S)-2-pyrrolidinemethanol (3.96 g) in THF (30 ml) is added2-chlorobenzothiazole (6.50 g) also in THF (80 ml) and then, dropwise,triethylamine (3.96 g). Stir at 50° C. for 4 hours. Cool to roomtemperature and filter out the solid. Evaporate the solvent and dissolvethe crude product in 5 ml of methylene chloride. Pass through a silicaplug (50 g) in a fritted filter funnel, and elute withmethanol/methylene chloride (10:90), applying suction until the producthas been collected. The yield of(S)-1-(2-benzothiazolyl)-2-hydroxymethylpyrrolidine is 8.8 g.

Example 3

[0198] To (R)-2-pyrrolidinemethanol (10.1 g) in THF (50 ml) is added4,5-dimethylthiazole (14.8 g) also in THF (100 ml) and then, dropwise,triethylamine (10.1 g). Stir at 50° C. for 4 hours. Cool to roomtemperature and filter out the solid. Evaporate the solvent and dissolvethe crude product in lOml of methylene chloride. Pass through a silicaplug (10 g) in a fritted filter funnel, and elute withmethanol/methylene chloride (10:90), applying suction until the producthas been collected. The yield of(R)-1-(4,5-dimethyl-2-thiazolyl)-2-hydroxymethylpyrrolidine is 19.5 g.

Example 4

[0199] 2-chloropyridine (12 g) and 2-(methylamino)ethanol (lOOml) arestirred under nitrogen at 120° C. for 18 hours. Cool to room temperatureand then pour into iced water (250 ml). Extract with ethyl acetate(2×200 ml). Dry over sodium sulfate. Filter. Evaporate to dryness. Thecrude product is distilled in vacuo to give 10.3 g ofN-methyl-N-(2-pyridinyl)-2-aminoethanol, boiling at 11020 C./1.0 mmHg.

Example 5

[0200] A solution of 2-chlorobenzoxazole (15.3 g) in THF (100 ml) isadded dropwise to an ice-cold solution of 2-(methylamino)ethanol (8.0 g)and triethylamine (10.1 g) also in THF (100 ml). The mixture is stirredat room temperature for 4 hours and the solid is filtered off. Thesolvent is evaporated and the residue is dissolved in methylene chlorideand passed through a silica plug (100 g), eluting withmethanol/methylene chloride (10:90) until the product has beencollected. The yield of N-methyl-N-(2-benzoxazolyl)-2-aminoethanol is15.7 g.

Example 6

[0201] Thionyl chloride (2.5 ml) was added dropwise to an ice-coldsolution of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-ylcarbinol (5.1g) in anhydrous methylene chloride (50 ml). The solution was stirred at0° C. for 1 hour and then at room temperature for another period of 2hours. Wash with saturated sodium bicarbonate solution (2×25 ml), thenwith brine (25 ml), and then with water (25 ml). Dry over sodiumsulfate, filter, and evaporate to dryness. The crude product,(R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethyl chloride (5.2 g) isused as is in the next step.

Example 7

[0202] Thionyl chloride (2.5 ml) was added dropwise to an ice-coldsolution of (S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-ylcarbinol (5.1g) in anhydrous methylene chloride (50 ml). The solution was stirred at0° C. for 1 hour and then at room temperature for another period of 2hours. Wash with saturated sodium bicarbonate solution (2×25 ml), thenwith brine (25 ml), and then with water (25 ml). Dry over sodiumsulfate, filter, and evaporate to dryness. The crude product,(S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethyl chloride (5.0 g) isused as is in the next step.

Example 8

[0203] A mixture of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethylchloride (8.43 g), triethylamine (2.6 g), and 2-(methylamino)ethanol (40ml) is stirred at 120° C. under nitrogen for 16 hours. Cool to roomtemperature and pour into iced water (100 ml). Extract with ethylacetate (3×100 ml) and wash the combined organic extracts with brine(100 ml). Dry over sodium sulfate. Filter. Evaporate to dryness. Theproduct,(R)-2-[N-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethyl)-N-methylamino]ethanolweighs 9.0 g.

Example 9

[0204] A mixture of (S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethylchloride (8.43 g), triethylamine (2.6 g), and 2-(methylamino)ethanol (40ml) is stirred at 120° C. under nitrogen for 16 hours. Cool to roomtemperature and pour into iced water (100 ml). Extract with ethylacetate (3×100 ml) and wash the combined organic extracts with brine(100 ml). Dry over sodium sulfate. Filter. Evaporate to dryness. Theproduct,(S)-2-[N-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethyl)-N-methylamino]ethanolweighs 8.9 g.

Example 10

[0205] A mixture of 2-chlorobenzoxazole (3.7 g), (L)-proline methylester, hydrochloride salt (4.0 g), and triethylamine (4.9 g) inanhydrous THF (50 ml) is stirred at room temperature for 18 hours. Thesolid is filtered off and washed with THF (10 ml). The solution isevaporated to dryness and the crude product is dissolved in methylenechloride (5 ml) and passed through a plug of silica (50 g), eluting withethyl acetate/methylene chloride (10:90). The product,(L)-N-(2-benzoxazolyl)-proline methyl ester (5.0 g) is a crystallinesolid.

Example 11

[0206] A mixture of 2-chlorobenzoxazole (3.7 g), (D)-proline methylester, hydrochloride salt (4.0 g), and triethylamine (4.9 g) inanhydrous THF (50 ml) is stirred at room temperature for 18 hours. Thesolid is filtered off and washed with THF (10 ml). The solution isevaporated to dryness and the crude product is dissolved in methylenechloride (5 ml) and passed through a plug of silica (50 g), eluting withethyl acetate/methylene chloride (10:90). The product,(D)-N-(2-benzoxazolyl)-proline methyl ester (5.5 g) is a crystallinesolid.

Example 12

[0207] (L)-N-(2-benzoxazolyl)-proline methyl ester (5.0 g) is suspendedin a mixture consisting of methanol (50 ml), water (5 ml), and lithiumhydroxide (0.5 g). Stir for 18 hours at room temperature. Acidify to pH4.5 with citric acid. Extract with ethyl acetate (4×50 ml). Dry oversodium sulfate, filter, and evaporate to dryness. The product,(L)-N-(2-benzoxazolyl)-proline (4.3 g) is an off-white solid.

Example 13

[0208] A mixture of (L)-proline (4.6 g), 2-chlorobenzoxazole (6.6 g),and triethylamine (4.45 g) in anhydrous THF (100 ml) is stirred atreflux temperature for 18 hours. Cool down to room temperature, filteroff the solid and wash it with a THF (10 ml). Evaporate the solvent. Addethyl acetate (50 ml) and then 1N sodium hydroxide (50 ml). Stir for 5minutes. Keep the aqueous phase. Wash again with ethyl acetate (50 ml).Acidify with citric acid to pH 4.5. Isolate the precipitate byfiltration. The aqueous filtrate is extracted with ethyl acetate (4×30ml). Dry over sodium sulfate. Filter. Evaporate to dryness. The solidsare dried in vacuo at 35° C. for 18 hours. The first crop of productweighs 4.77 g. The second crop weighs 3.26 g. The total amount ofproduct, (L)-N-(2-benzoxazolyl)-proline, is 8.03 g.

Example 14

[0209] A mixture of (D)-proline (4.6 g), 2-chlorobenzoxazole (6.6 g),and triethylamine (4.45 g) in anhydrous THF (100 ml) is stirred atreflux temperature for 18 hours. Cool down to room temperature, filteroff the solid and wash it with a THF (10 ml). Evaporate the solvent. Addethyl acetate (50 ml) and then 1N sodium hydroxide (50 ml). Stir for 5minutes. Keep the aqueous phase. Wash again with ethyl acetate (50 ml).Acidify with citric acid to pH 4.5. Isolate the precipitate byfiltration. The aqueous filtrate is extracted with ethyl acetate (4×30ml). Dry over sodium sulfate. Filter. Evaporate to dryness. The solidsare dried in vacuo at 35° C. for 18 hours. The first crop of productweighs 4.93 g. The second crop weighs 2.90 g. The total amount ofproduct, (L)-N-(2-benzoxazolyl)-proline, is 7.83 g.

Example 15

[0210] A mixture of 4-hydroxybenzaldehyde (122.12 g),2,4-thiazolidinedione (117.13 g), piperidine (5.11 g), and benzoic acid(6.11 g) in toluene (1,000 ml), is stirred at 80° C. for 16 hours. Coolto room temperature and filter off the yellow solid. Wash the solid withmethylene chloride (3×100 ml) and then with methanol/methylene chloride(30:70) (2×100 ml). Dry in vacuo at 35° C. until constant weight. Theyield of product, 5-(4-hydroxybenzylidene)-2,4-thiazolidinedione, is217.8 g.

Example 16

[0211] To p-anisidine (25 g) in acetone (400 ml) at between 0 and 5° C.,add dropwise a solution of sodium nitrite (15.41 g) in water (50 ml) and12N hydrochloric acid (50 ml) from 2 different funnels over a 15-minuteperiod. Stir for another 5 minutes at 0° C. Add methyl acrylate (104.9g) and then warm up the solution to 35° C. Transfer into a 2-LErlenmeyer flask and stir vigorously. While stirring, add copper(I)oxide (0.7 g) in several portions. Keep stirring for as long as nitrogengas evolves from the solution, then stir for another 4 hours. Evaporatethe organic solvent and dilute the aqueous residue with water (200 ml).Extract with methylene chloride (200 ml). Dry over sodium sulfate,filter, and evaporate to dryness. The product, methyl2-chloro-3-(4-methoxyphenyl)propanoate, is a dark oil weighing 42.96 g.

Example 17

[0212] Methyl 2-chloro-3-(4-methoxyphenyl)propanoate (31.44 g), thiourea(16.89 g), and anhydrous sodium acetate (11.24 g) in 2-methoxyethanol(100 ml) is stirred at 100° C. for 4 hours. Cool to room temperature andplace the flask at 4° C. for 16 hours. The pale yellow solid is filteredoff and is washed with hexanes (50 ml). Stir for 30 minutes in ethylacetate/water (100 ml:10 ml). Filter. Crystallize from hot ethanol (600ml). After leaving at 4° C. for 16 hours, the crystals are filtered offand stirred at reflux for 8 hours in a mixture of 2-methoxyethanol (100ml) and 2N hydrochloric acid (20 ml). Evaporate the solvent. Add ethylacetate (200 ml) and water (200 ml). Keep the organic phase and washagain with water (200 ml). Dry over sodium sulfate, filter, evaporate todryness. The product, 5-(4-methoxybenzyl)thiazolidine-2,4-dione (16.7 g)is an oil that solidifies upon standing.

Example 18

[0213] To a solution of 5-(4-methoxybenzyl)thiazolidine-2,4-dione (14.3g) in anhydrous methylene chloride (100 ml) cooled to −40° C., add a 1.0M solution of boron tribromide in methylene chloride (63 ml). Thesolution is left to warm up to 23° C. and is then stirred for another 16hours. Pour into iced water (700 ml) and stir for 15 minutes. Isolatethe precipitate by filtration. Wash the product with water (50 ml) andthen with methylene chloride (50 ml). The yield of5-(4-hydroxybenzyl)thiazolidine-2,4-dione is 12.8 g.

Example 19

[0214] A mixture of methyl 4-formylbenzoate (164.16 g),2,4-thiazolidinedione (117.13 g), piperidine (5.11 g), and benzoic acid(6.11 g) in toluene (1,000 ml), is stirred at 80° C. for 16 hours. Coolto room temperature and filter off the yellow solid. Wash the solid withmethylene chloride (3×100 ml) and then with methanol/methylene chloride(30:70) (2×100 ml). Dry in vacuo at 35° C. until constant weight. Theyield of product, 5-(4-carbomethoxybenzylidene)-2,4-thiazolidinedione,is 258.0 g.

Example 20

[0215] A suspension of5-(4-carbomethoxybenzylidene)-2,4-thiazolidinedione (26.3 g) andmagnesium turnings (24 g) in anhydrous methanol (300 ml) is stirred at45° C. for 8 hours. Acidify to pH 5.0 with 6N HCl and then extract withmethylene chloride (2×250 ml). Dry over sodium sulfate, filter, andevaporate to dryness. The crude product is chromatographed on silica gel(1,300 g), eluting with methanol/methylene chloride (02:98). The yieldof 5-(4-carbomethoxybenzyl)-2,4-thiazolidinedione is 15.2 g.

Example 21

[0216] A suspension of5-(4-carbomethoxybenzylidene)-2,4-thiazolidinedione (50 g) in 6N HCl(200 ml) is stirred at reflux for 4 hours. The mixture is cooled to 4°C. and the product is filtered off. The product is then washed withwater (2×100 ml) and is dried in vacuo at 40° C. The yield of5-(4-carboxybenzylidene)-2,4-thiazolidinedione is 45 g.

Example 22

[0217] A suspension of 5-(4-carbomethoxybenzyl)-2,4-thiazolidinedione(50 g) in 6N HCl (200 ml) is stirred at reflux for 4 hours. The mixtureis cooled to 4° C. and the product is filtered off. The product is thenwashed with water (2×100 ml) and is dried in vacuo at 40° C. The yieldof 5-(4-carboxybenzyl)-2,4-thiazolidinedione is 44 g.

Example 23

[0218] (R)-6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (9.2g) and 5-(4-hydroxybenzyl)thiazolidine-2,4-dione (8.3 g) are dissolvedin methylene chloride (100 ml) and THF (50 ml). To this adddicyclohexylcarbodiimide (7.6 g) and DMAP (0.5 g), and then stir for 4hours at room temperature. The solid is removed by filtration and iswashed with a small amount of THF (20 ml). The solvent is removed andthe solid residue is stirred with methylene chloride (100 ml) and leftat 4° C. for 16 hours. The product is isolated by filtration and driedin vacuo at 23° C. The yield of5-{4-[(R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxy]benzyl}thiazolidine-2,4-dioneis 12.4 g.

Example 24

[0219] (S)-6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (9.2g) and 5-(4-hydroxybenzyl)thiazolidine-2,4-dione (8.3 g) are dissolvedin methylene chloride (100 ml) and THF (50 ml). To this adddicyclohexylcarbodiimide (7.6 g) and DMAP (0.5 g), and then stir for 4hours at room temperature. The solid is removed by filtration and iswashed with a small amount of THF (20 ml). The solvent is removed andthe solid residue is stirred with methylene chloride (100 ml) and leftat 4° C. for 16 hours. The product is isolated by filtration and driedin vacuo at 23° C. The yield of5-{4-[(S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxy]benzyl}thiazolidine-2,4-dione is 13.3 g.

Example 25

[0220] (R)-6-Hydroxy-2,5,7,8-tetramethylchroman-2-carbinol (1.9 g) and5-(4-carboxybenzyl)thiazolidine-2,4-dione (1.8 g) are dissolved inmethylene chloride (20 ml) and THF (10 ml). To this adddicyclohexylcarbodiimide (1.6 g) and DMAP (0.1 g), and then stir for 4hours at room temperature. The solid is removed by filtration and iswashed with a small amount of THF (5 ml). The solvent is removed and thesolid residue is stirred with methylene chloride (20 ml) and left at 4°C. for 16 hours. The product is isolated by filtration and dried invacuo at 23° C. The yield of5-{4-[(R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-methoxy]benzyl}thiazolidine-2,4-dioneis 2.54 g.

Example 26

[0221] (S)-6-Hydroxy-2,5,7,8-tetramethylchroman-2-carbinol (1.9 g) and5-(4-carboxybenzyl)thiazolidine-2,4-dione (1.8 g) are dissolved inmethylene chloride (20 ml) and THF (10 ml). To this adddicyclohexylcarbodiimide (1.6 g) and DMAP (0.1 g), and then stir for 4hours at room temperature. The solid is removed by filtration and iswashed with a small amount of THF (5 ml). The solvent is removed and thesolid residue is stirred with methylene chloride (20 ml) and left at 4°C. for 16 hours. The product is isolated by filtration and dried invacuo at 23° C. The yield of 5-{4-[(S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-methoxy]benzyl}thiazolidine-2,4-dioneis 2.17 g.

Example 27

[0222] (R)-6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (4.6g) and 5-(4-hydroxybenzylidene)thiazolidine-2,4-dione (4.2 g) aredissolved in methylene chloride (50 ml) and THF (25 ml). To this adddicyclohexylcarbodiimide (3.8 g) and DMAP (0.25 g), and then stir for 4hours at room temperature. The solid is removed by filtration and iswashed with a small amount of THF (10 ml). The solvent is removed andthe solid residue is stirred with methylene chloride (50 ml) and left at4° C. for 16 hours. The product is isolated by filtration and dried invacuo at 23° C. The yield of5-{4-[(R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxy]benzylidene}thiazolidine-2,4-dioneis 5.9 g.

Example 28

[0223] (S)-6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (4.6g) and 5-(4-hydroxybenzylidene)thiazolidine-2,4-dione (4.2 g) aredissolved in methylene chloride (50 ml) and THF (25 ml). To this adddicyclohexylcarbodiimide (3.8 g) and DMAP (0.25 g), and then stir for 4hours at room temperature. The solid is removed by filtration and iswashed with a small amount of THF (10 ml). The solvent is removed andthe solid residue is stirred with methylene chloride (50 ml) and left at4° C. for 16 hours. The product is isolated by filtration and dried invacuo at 23° C. The yield of 5-{4-[(S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxy]benzylidene}thiazolidine-2,4-dioneis 6.2 g.

Example 29

[0224] (R)-6-Hydroxy-2,5,7,8-tetramethylchroman-2-carbinol (3.8 g) and5-(4-carboxybenzylidene)thiazolidine-2,4-dione (3.6 g) are dissolved inmethylene chloride (40 ml) and THF (20 ml). To this adddicyclohexylcarbodiimide (3.2 g) and DMAP (0.2 g), and then stir for 4hours at room temperature. The solid is removed by filtration and iswashed with a small amount of THF (10 ml). The solvent is removed andthe solid residue is stirred with methylene chloride (40 ml) and left at4° C. for 16 hours. The product is isolated by filtration and dried invacuo at 23° C. The yield of5-{4-[(R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-methoxy]benzylidene}thiazolidine-2,4-dione is 5.4 g.

Example 30

[0225] (S)-6-Hydroxy-2,5,7,8-tetramethylchroman-2-carbinol (3.8 g) and5-(4-carboxybenzylidene)thiazolidine-2,4-dione (3.6 g) are dissolved inmethylene chloride (40 ml) and THF (20 ml). To this adddicyclohexylcarbodiimide (3.2 g) and DMAP (0.2 g), and then stir for 4hours at room temperature. The solid is removed by filtration and iswashed with a small amount of THF (10 ml). The solvent is removed andthe solid residue is stirred with methylene chloride (40 ml) and left at4° C. for 16 hours. The product is isolated by filtration and dried invacuo at 23° C. The yield of5-{4-[(S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-methoxy]benzylidene}thiazolidine-2,4-dioneis 5.2 g.

Example 31

[0226] (L)-N-(2-benzoxazolyl)-proline (3.26 g) and 5-(4-hydroxybenzyl)thiazolidine-2,4-dione (3.1 g) are suspended in methylene chloride (100ml). Add DCC (2.89 g) and DMAP (0.12 g) and stir at room temperature for4 hours. Filter and purify on 114 g of silica, eluting withmethanol/methylene chloride (02:98). The yield of 5-{4-[(S)-1-(2-benzoxazolyl)pyrrolidne-2-carboxy]benzyl}thiazolidine-2,4-dione is4.55 g.

Example 32

[0227] (L)-1-(2-benzoxazolyl)pyrrolidine-2-carbinol (3.26 g) and5-(4-carboxybenzyl)thiazolidine-2,4-dione (3.25 g) are suspended inmethylene chloride (100 ml). Add DCC (2.88 g) and DMAP (0.12 g) and stirat room temperature for 4 hours. Filter and purify on 132 g of silica,eluting with methanol/methylene chloride (02:98). The yield of5-{4-[(S)-1-(2-benzoxazolyl)pyrrolidinyl-2-methoxycarbonyl]benzyl}-thiazolidine-2,4-dioneis 4.68 g.

Example 33

[0228] (D)-1-(2-benzoxazolyl)pyrrolidine-2-carbinol (3.26 g) and5-(4-carboxybenzylidene)thiazolidine-2,4-dione (3.35 g) are suspended inmethylene chloride (100 ml). Add DCC (2.91 g) and DMAP (0.12 g) and stirat room temperature for 4 hours. Filter and purify on 108 g of silica,eluting with methanol/methylene chloride (02:98). The yield of5-{4-[(R)-1-(2-benzoxazolyl)pyrrolidinyl-2-methoxycarbonyl]benzylidene}-thiazolidine-2,4-dioneis 4.32 g.

Example 34

[0229] (D)-1-(2-benzoxazolyl)pyrrolidine-2-carbinol (3.26 g) and5-(4-carboxybenzyl)thiazolidine-2,4-dione (3.25 g) are suspended inmethylene chloride (100 ml). Add DCC (2.93 g) and DMAP (0.12 g) and stirat room temperature for 4 hours. Filter and purify on 162 g of silica,eluting with methanol/methylene chloride (02:98). The yield of5-{4-[(S)-1-(2-benzoxazolyl)pyrrolidinyl-2-methoxycarbonyl]benzyl}-thiazolidine-2,4-dioneis 4.77 g.

Example 35

[0230] Triethylamine (8.3 ml) is added dropwise to a stirred coldsolution of ethyl 2-aminoacetoacetate hydrochloride (5.4 g) and4-methoxybenzoyl chloride (5.2 g) in dichloromethane (100 ml). Afterstirring for 3 hours, the solution is washed with water (100 ml), driedover sodium sulfate, filtered, and evaporated to dryness. The crudeproduct, ethyl 2-(4-methoxy)phenylaminoacetoacetate weighs 6.7 g.

Example 36

[0231] Ethyl 2-(4-methoxy)phenylaminoacetoacetate (5.9 g) and phosphorusoxychloride (50 ml) are stirred at 100° C. for 30 minutes. Thephosphorus oxychloride is removed by evaporation, and the residue isdiluted with aqueous sodium bicarbonate and extracted with methylenechloride. After drying over sodium sulfate, the solution is evaporatedand the product is crystallized from hexane, giving ethyl5-methyl-2-(4-methoxy)phenyl-4-oxazolecarboxylate (4.5 g).

Example 37

[0232] A solution of benzoyl chloride (17 g) in ethyl acetate (40 ml) isadded dropwise, with stirring, in an ice-cold mixture of L-serine methylester, hydrochloride (15.5 g), water (100 ml), sodium bicarbonate (21.8g), and ethyl acetate (100 ml). After stirring for 2 hours, the organicphase is separated, dried over sodium sulfate, and evaporated to givecrystalline N-benzoyl-L-serine methyl ester (22.0 g).

Example 38

[0233] A stirred mixture of N-benzoyl-L-serine methyl ester (21.0 g),thionyl chloride (21.0 g), and methylene chloride (150 ml) is stirred atreflux for 1 hour. The solvent is evaporated and the residue is dilutedwith cold water. Neutralize with sodium bicarbonate, and extract withethyl acetate. Purification on silica gel (250 g), eluting withmethanol:methylene chloride (01:99), yields methyl(S)-2-phenyl-2-oxazoline-4-carboxylate (15.2 g).

Example 39

[0234] A solution of benzoyl chloride (17 g) in ethyl acetate (40 ml) isadded dropwise, with stirring, in an ice-cold mixture of L-threoninemethyl ester, hydrochloride (16.5 g), water (100 ml), sodium bicarbonate(21.8 g), and ethyl acetate (100 ml). After stirring for 2 hours, theorganic phase is separated, dried over sodium sulfate, and evaporated togive crystalline N-benzoyl-L-threonine methyl ester (21.5 g).

Example 40

[0235] A stirred mixture of N-benzoyl-L-threonine methyl ester (21.0 g),thionyl chloride (21.0 g), and methylene chloride (150 ml) is stirred atreflux for 1 hour. The solvent is evaporated and the residue is dilutedwith cold water. Neutralize with sodium bicarbonate, and extract withethyl acetate. Purification on silica gel (250 g), eluting withmethanol:methylene chloride (01:99), yields methyl(R,S)-2-phenyl-2-oxazoline-5-methyl-4-carboxylate (14.8 g).

Example 41

[0236] Activity in NIDDM KK-A^(y) male mice. Non-inslin dependentdiabetic mellitus male mice, weighing 50+/−5 g (9-10 weeks of age) wereused. These animals exhibited hyperinsulinemia, hyperglycemia, and isletatrophy. The test compounds 105, 115, and 155, and the positive controlcompound troglitazone were suspended in a 1% carboxymethylcellulosepreparation and were given orally at a dose of 10 mg/kg, twice a day,for 5 consecutive days. Blood sampling was performed before the firstdose and then 90 minutes after the last dose. Serum glucose and insulinlevels were measured. Percent reduction of serum glucose and insulinlevels relative to the pre-treatment values are shown in Table XX andFIGS. 20 and 21.

Example 42—CYP assays

[0237] A series of assays to test for activity of 5 principal drugmetabolizing enzymes, CYP1A4, CYP2C9, CYP2Cl9, CYP2D6, and CYP3A4, aswell as other CYP450 subfamilies, have been designed and are nowcommercially available either as ready-to-use kits or as contract work.Commercial sources for these assays include for example Gentest and MDSPanlabs. These assays can test for activity of the enzyme towardmetabolism of the test compound as well as testing for kineticmodification (inhibition or activation) of the enzyme by the substrate.These in vitro protocols use simple rapid, low cost methods tocharacterize aspects of drug metabolism and typically require less than1 mg of test material.

Example 43—High Throughput Cytochrome P450 Inhibition Screen

[0238] The majority of drug-drug interactions are metabolism-based andof these, most involve CYP450. For example, if a new chemical entity isa potent CYP450 inhibitor, it may inhibit the metabolism of aco-administered medication, potentially leading to adverse clinicalevents. The inhibition of human CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6,CYP3A4 and other isoforms are assessed using microsomal preparations asenzyme sources and the fluorescence detection method described in theliterature (Crespi, C. L., et al. (1997) Microtiter plate assays forinhibition of human, drug-metabolizing cytochromes P450. Anal. Biochem.248:188-190; Crespi, C. L., et al. (1999) Novel High throughputfluorescent cytochrome P450 assays. Toxicol. Sci. 48, abstr. No.323;Favreau, L. V., et al. (1999) Improved Reliability of the RapidMicrotiter Plate Assay Using Recombinant Enzyme in Predicting CYP2D6Inhibition in Human Liver Microsomes. Drug Metab. Dispos. 27:436-439).Tests are conducted in 96-well microtiter plates and may use thefollowing fluorescent CYP450 substrates: resorufin benzyl ether (BzRes),3-cyano-7-ethoxycoumarin (CEC), ethoxyresorufin (ER),7-methoxy-4-trifluoromethylcoumarin (MFC),3-[2-(N,N-diethyl-N-methylamino)ethyl]-7-methoxy-4-methylcoumarin(AMMC), 7-benzyloxyquinoline (BQ), dibenzyfluorescein (DBF) or7-benzyloxy-4-trifluoromethylcoumarin (BFC). Multiple CYP3A4 substratesare available to assess substrate dependence of IC₅₀ values, activationand the complex inhibition kinetics associated with this enzyme(Korzekwa, K. R., et al. (1998). Evaluation of atypical cytochrome P450kinetics with two-substrate models: evidence that multiple substratescan simultaneously bind to the cytochrome P450 active sites.Biochemistry., 37, 4137-4147; Crespi, C. L. (1999) Higher-throughputscreening with human cytochromes P450. Curr. Op. Drug Discov. Dev.2:15-19). Data are reported as IC₅₀ values or percent inhibition whenusing only one or two concentrations of test compound.

Example 44—Metabolic Stability

[0239] Metabolic stability influences both oral bioavailability andhalf-life; compounds of higher metabolic stability are less controllablein their pharmacokinetic parameters. This combination ofcharacteristics, or properties, leads to potential DDI and livertoxicity. This test measures the metabolic stability of the compound inthe presence of CYP450, in the presence of hydrolytic enzymes, and inthe presence of both CYP450 and hydrolytic enzymes.

[0240] Stability in the presence of CYP450: With CYP450 substrates oflow and moderate in vivo clearance, there is a good correlation betweenin vitro metabolic stability and in vivo clearance (Houston, J. B.(1994) Utility of in vitro drug metabolism data in predicting in vivometabolic clearance). This test uses pooled liver microsomes, S9 (humanand/or preclinical species) or microsomal preparations with appropriatepositive and negative controls. Assessment of both phase-I and phase-IIenzymatic metabolism is possible, and a standard set of substrateconcentrations and incubations may be used. Metabolism is measured byloss of parent compound HPLC analysis with absorbance, fluorescence,radiometric or mass spectrometric detection can be used.

[0241] Stability in the presence of hydrolytic enzymes: Hydrolyticenzymes in liver cytosol, plasma, or enzymatic mixes from commercialsources (human and/or preclinical species) are used to assess themetabolic stability of the novel compounds of the invention. Appropriatepositive and negative controls, as well as a standard set of substrateconcentrations, are added in order to correlate in vitro observationswith in vivo metabolic half-life. Metabolism is measured by loss ofparent compound. HPLC analysis with absorbance, fluorescence,radiometric or mass spectrometric detection can also be used.

[0242] Stability in the presence of both CYP450 and hydrolytic enzymes:This test uses pooled liver microsomes, S9 (human and/or preclinicalspecies) or microsomal preparations with appropriate positive andnegative controls, combined with hydrolytic enzymes from commercialsources, plasma, or cytosol to assess metabolic stability. The test canalso be performed in primary hepatocytes (human and/or preclinicalspecies) or in perfused liver (preclinical species). The use of positiveand negative controls, as well as a standard set of substrates allow forcorrelations between in vitro observations and in vivo metabolichalf-life.

Example 45—CYP1A1 Induction Screening

[0243] Induction of CYP1A1 is indicative of ligand activation of thearyl hydrocarbon (Ah) receptor, a process associated with induction of avariety of phase-I and phase-II enzymes (Swanson, H. I. (1993) TheAH-receptor: genetics, structure and methylene chloride (50 ml). Thesolution was stirred at 0° C. for 1 hour and then at function.Pharmacogenetics 3:213-230). Many pharmaceutical companies choose toavoid development of compounds suspected as Ah-receptor ligands. Thistest uses a human lymphoblastoid cell line containing native CYP1A1activity that is elevated by exposure to Ah receptor ligands. Assays areconducted in 96-well microtiter plates using an overnight incubationwith the test substances, followed by addition of7-ethoxy-4-trifluoromethylcoumarin as substrate. Dibenz(a,h)anthraceneis used as a positive control inducer. A concurrent control test fortoxicity or CYP1A1inhibition is available using another cell line thatconstitutively expresses CYP1A1.

Example 46—Cytochrome P450 Reaction Phenotyping

[0244] The number and identity of CYP450 enzymes responsible for themetabolism of a drug affects population variability in metabolism.Reaction phenotyping uses either liver microsomes with selectiveinhibitors or a panel of cDNA-expressed enzymes to provide a preliminaryindication of the number and identity of enzymes involved in themetabolism of the substrate. The amount of each cDNA-expressed enzyme ischosen to be proportional to the activity of the same enzyme in pooledhuman liver microsomes. Protein concentration is standardized by theaddition of control microsomes (without CYP450 enzymes). A standard setof substrate concentrations and incubations is used and metabolism ofthe drug is measured by loss of parent compound. Alternatively, HPLCanalysis with absorbance, fluorescence, radiometric or massspectrometric detection can be used.

Example 47—Drug Permeability Measurement in Caco-2, LLC-PK1 or MDCK CellMonolayers

[0245] Drug permeability through cell monolayers correlates well withintestinal permeability and oral bioavailability. Several mammalian celllines are appropriate for this measurement (Stewart, B. H., et al.(1995) Comparison of intestinal permeabilities determined in multiple invitro and in situ models: relationship to absorption in humans. Pharm.Res. 12:693-699; Irvine, J. D., et al. (1999). MDCK (Madin-Darby CanineKidney) cells: A tool for membrane permeability screening. J. Pharm.Sci. 88:28-33). Apical to basolateral diffusion is measured using astandard set of time points and drug concentrations. These systems canbe adapted to a high throughput mode. Liquid chromatography/massspectroscopy (LC/MS) analysis is also available for analysis ofmetabolites. Controls for membrane integrity and comparator compoundsare included and data are reported as apparent permeability (P_(app)) orpercent flux under fixed conditions.

Example 48—Human P-glycoprotein (PGP) Screen

[0246] An ATPase assay is used to determine if the compounds interactwith the xenobiotic transporter MDR1 (PGP). ATP hydrolysis is requiredfor drug efflux by PGP, and the ATPase assay measures the phosphateliberated from drug-stimulated ATP hydrolysis in human PGP membranes.The assay screens compounds in a high throughput mode using singleconcentration determinations compared to the ATPase activity of a knownPGP substrate. A more detailed approach by determining theconcentration-dependence and apparent kinetic parameters of thedrug-stimulated ATPase activity, or inhibitory interaction with PGP canalso be used.

Example 49—PGP-Mediated Drug Transport in Polarized Cell Monolayers

[0247] P-glycoprotein (PGP) is a member of the ABC transportersuperfamily and is expressed in the human intestine, liver and othertissues. Localized to the cell membrane, PGP functions as anATP-dependent efflux pump, capable of transporting many structurallyunrelated xenobiotics out of cells. Intestinal expression of PGP mayaffect the oral bioavailability of drug molecules that are substratesfor this transporter. Compounds that are PGP substrates can beidentified by direct measurement of their transport across polarizedcell monolayers. Two-directional drug transport (apical to basolateralpermeability, and basolateral to apical PGP-facilitated efflux) can bemeasured in LLC-PK1 cells (expressing human PGP cDNA) and incorresponding control cells. Caco-2 cells can also be used.Concentration-dependence is analyzed for saturation of PGP-mediatedtransport, and apparent kinetic parameters are calculated. Testcompounds can also be screened in a higher throughput mode using thismodel. LC/MS analysis is available. Controls for membrane integrity andcomparator compounds are included in the assay system.

Example 50—Protein Binding

[0248] LC/MS analysis can be used to assess the affinity of the testcompound for immobilized human serum albumin (Tiller, P. R., et al.(1995) Immobilized human serum albumin: Liquid chromatography/massspectrometry as a method of determining drug-protein binding. Rapidcomm. mass spectrom. 9:261-263). Appropriate low, medium and highbinding positive control comparators are included in the test.

Example 51—Metabolite Production

[0249] Milligram quantities of metabolites can be produced usingmicrosomal preparations or cell lines. These metabolites can be used asanalytical standards, an aid in structural characterization, or asmaterial for toxicity and efficacy testing.

Example 52—Effect on Herg Channel

[0250] This assay tests the effect of parent drugs and metabolite(s) onHerg channels using either a cloned Herg channel expressed in stablehuman embryonic kidney cells (HEK), or Chinese hamster ovary cells (CHO)transiently expressing the Herg/MiRP-1-encoded potassium channel. Wholecell experiments are carried out by means of the patch-clamp techniqueand performed in the voltage-clamp mode.

[0251] In the test using HEK cells, cells are depolarized from theholding potential of −80mV to voltages between −80 and +60 mV in 10 mVincrements for 4 seconds in order to fully open and inactivate thechannels. The voltage is then stepped back to −50 mV for 6 seconds inorder to record the tail current. The current is also recorded in thepresence of test compounds in order to evaluate a dose-response curve ofthe ability of a test compound to inhibit the Herg channel.

[0252] In the test involving CHO cells, the cells are clamped at aholding potential of −60 mV in order to establish the whole-cellconfiguration. The cells are then depolarized to +40 mV for 1 second andafterwards hyper-/depolarized to potentials between −120 and +20mV in 20mV increments for 300 mSec in order to analyze the tail currents. Toinvestigate the effects of test compounds, the cells are depolarized for300 mSec to +40 mV and then repolarized to −60 mV at a rate of0.5mV/mSec, followed by a 200-mSec test potential to −120 mV. After 6control stimulations, the extracellular solution is changed to asolution containing the test compound, and 44 additional stimulationsare then performed. The peaks of the outward currents and inward tailcurrents are analyzed.

[0253] Activity on HERG channel can also be assessed using a perfusedheart preparation, usually guinea pig heart or other small animal. Inthis assay the heart is paced and perfused with a solution containing aknown concentration of the drug. A concentration-response curve of theeffects of drug on QT interval is then recorded and compared to a blankpreparation in which the perfusate does not contain the drug.

Example 53—Toxicity in Hepatocyte Cell Culture

[0254] This test is performed in primary human and porcine hepatocytecultures. Toxicity is determined by the measurement of total proteinsynthesis by pulse-labeling with [¹⁴C]leucine (Kostrubsky, V. E., et al.(1997) Effect of taxol on cytochrome P450 3A and acetaminophen toxicityin cultured rat hepatocytes: Comparison to dexamethasone. Toxicol. Appl.Pharmacol. 142:79-86), and by reduction of3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide using aprotocol described by the manufacturer (Sigma Chemical Co., St. Louis,Mo.). Hepatocytes can be isolated from livers not used for whole organtransplants or from male Hanford miniature pigs.

[0255] It should be understood that the reaction schemes and embodimentsdescribed herein are for illustrative purposes only and that variousmodifications or changes in light thereof will be suggested to personsskilled in the art and are to be included within the spirit and purviewof this application and the scope of the appended claims. TABLE IFormula I

Compound P number X and Q*  1  2

H db  3  4

H db  5  6

H db  7  8

H db  9 10

H db 11 12

H db 13 14

H db 15 16

H db 17 18

H db 19 20

H db 21 22

H db 23 24

H db 25 26

H db 27 28

H db 29 30

H db 31 32

H db

[0256] TABLE II Formula II

Compound number Z R1 R2 R3 33 O

H H 34 O

CH3 H 35 O

CH3 CH3 36 S

CH3 H 37 O

CH3 H 38 S

CH3 H 39 O

CH3 H 40 S

CH3 H 41 O

CH3 H 42 S

CH3 H 43 O

H H 44 O

CH3 H 45 S

H H 46 O

CH3 H 47 S

H H 48 O

CH3 H 49 O

CH3 H 50 O

CH3 H

[0257] TABLE III

Compound number Z R1 R2 R3 51 O

H H 52 O

CH3 H 53 O

CH3 CH3 54 S

CH3 H 55 O

CH3 H 56 S

CH3 H 57 O

CH3 H 58 S

CH3 H 59 O

CH3 H 60 S

CH3 H 61 O

H H 62 O

CH3 H 63 S

H H 64 O

CH3 H 65 S

H H 66 O

CH3 H 67 O

CH3 H 68 O

CH3 H

[0258] TABLE IV

Compound number Z R1 R2 R3 69 O

H H 70 O

CH3 H 71 O

CH3 CH3 72 S

CH3 H 73 O

CH3 H 74 S

CH3 H 75 O

CH3 H 76 S

CH3 H 77 O

CH3 H 78 S

CH3 H 79 O

H H 80 O

CH3 H 81 S

H H 82 O

CH3 H 83 S

H H 84 O

CH3 H 85 O

CH3 H 86 O

CH3 H

[0259] TABLE V

Compound number Z R1 R2 R3 87 O

H H 88 O

CH3 H 89 O

CH3 CH3 90 S

CH3 H 91 O

CH3 H 92 S

CH3 H 93 O

CH3 H 94 S

CH3 H 95 O

CH3 H 96 S

CH3 H 97 O

H H 98 O

CH3 H 99 S

H H 100  O

CH3 H 101  S

H H 102  O

CH3 H 103  O

CH3 H 104  O

CH3 H

[0260] TABLE VI

Compound number Y 105

106

107

108

109

110

111

112

113

114

[0261] TABLE VII

Compound number Y 115

116

117

118

119

120

121

122

123

124

[0262] TABLE VIII

Compound number Y 125

126

127

128

129

130

131

132

133

134

[0263] TABLE IX

Compound number Y 135

136

137

138

139

140

141

142

143

144

[0264] TABLE X

Compound number Y 145

146

147

148

149

150

151

152

153

154

[0265] TABLE XI

Compound number Y 155

156

157

158

159

160

161

162

163

164

[0266] TABLE XII

Compound number Y 165

166

167

168

169

170

171

172

173

174

[0267] TABLE XIII

Compound number Y 175

176

177

178

179

180

181

182

183

184

[0268] TABLE XIV

Compound number Y 185

186

187

188

189

190

191

192

193

194

[0269] TABLE XV

Compound number Y 195

196

197

198

199

200

201

202

203

204

[0270] TABLE XVI

Compound number Y 205

206

207

208

209

210

211

212

213

214

[0271] TABLE XVII

Compound number Y 215

216

217

218

219

220

221

222

223

224

[0272] TABLE XVIII

Compound number R4 R5 225

H 226

CH3 227

H 228

CH3 229

H 230

CH3 231

H 232

CH3 233

H 234

CH3 235

H 236

CH3 237

H 238

CH3 239

H 240

CH3 241

H 242

CH3

[0273] TABLE XIX

Compound number Fib P and Q* 243 244

H db 245 246

H db 247 248

H db

[0274] TABLE XX

Compound number Hetero P and Q* 249 250

H db 251 252

H db

[0275] TABLE XXI

Compound number NSAID P and Q* 253 254

H db 255 256

H db 257 258

H db 259 260

H db

[0276] TABLE XXII

Compound number X P and Q* 261 262

H db 263 264

H db 265 266

H db 267 268

H db

[0277] TABLE XXIII Activity in NIDDM Mice. Compound Serum Glucose (%)Serum Insulin (%) Vehicle 0 1 105 40 10 115 36 13 155 37 9 Troglitazone35 15

We claim:
 1. A compound comprising

wherein: A and B may be the same or different and are CH₂, CO, N, NO,NH, SO₀₋₂, or O; D₁-D₆ can be the same or different and are CH, N, S, orO; E can be a substituent attached to one or more of the atoms locatedat D₁-D₆; P and Q can be a double bond; or P, Q, and E can be the sameor different and are a moiety selected from the group consisting of H,C₁₋₁₀ alkyl, substituted alkyl groups, substituted or unsubstitutedcarboxylic acids, substituted or unsubstituted carboxylic esters,halogen, carboxyl, hydroxyl, phosphate, phosphonate, aryl, CN, OH, COOH,NO₂, NH₂, SO₂₋₄, C₁₋₂₀ heteroalkyl, C₂₋₂₀ alkenyl, alkynyl, akynyl-aryl,alkynyl-heteroaryl, aryl, C₁₋₂₀ alkyl-aryl, C₂₋₂₀ alkenyl-aryl,heteroaryl, C₁₋₂₀ alkyl-heteroaryl, C₂₋₂₀ alkenylheteroaryl, cycloalkyl,heterocycloalkyl, C₁₋₂₀ alkyl-heteroycloalkyl, and C₁₋₂₀alkylcycloalkyl, any of which may be, optionally, substituted with amoiety selected from the group consisting of C₁₋₆ alkyl, halogen, OH,NH₂, CN, NO₂, COOH, or SO₂₋₄; X is —OH, —COOH, or a substitutedcarboxylic group comprising OOC— or COO— and said substituted carboxylicgroup is attached to D₁; and analogs, derivatives, or salts of thecompound of Formula I.
 2. The compound according to claim 1, whereinsaid substituted carboxylic acid group is selected from the groupconsisting of alkyloxycarbonyl, alkylcarbonyloxy, aryloxycarbonyl,arylcarbonyloxy, heteroalkyloxycarbonyl, heteroalkylcarbonyloxy,heteroaryl-oxycarbonyl, heteroarylcarbonyloxy, each of which is,optionally, substituted with C₁₋₁₀ alkyl, CN, COOH, NO₂, NH₂, SO₂₋₄,C₁₋₂₀ heteroalkyl, C₂₋₂₀ alkenyl, alkynyl, akynyl-aryl,alkynyl-heteroaryl, aryl, C₁₋₂₀ alkylaryl, C₂₋₂₀ alkenyl-aryl,heteroaryl, C₁₋₂₀ alkyl-heteroaryl, C₂₋₂₀ alkenyl-heteroaryl,cycloalkyl, heterocycloalkyl, C₁₋₂₀ alkyl-heteroycloalkyl, and C₁₋₂₀alkyl-cycloalkyl, any of which may be, optionally, substituted with amoiety selected from the group consisting of C₁₋₆ alkyl, halogen, OH,NH₂, CN, NO₂, COOH, or SO₂₋₄.
 3. The compound according to claim 1,wherein said heterocyclic groups are selected from the group consistingof morpholine, triazole, imidazole, pyrrolidine, piperidine, piperazine,pyrrole, dihydropyridine, aziridine, thiazolidine, thiazoline,thiadiazolidine or thiadiazoline.
 4. The compound according to claim 2,wherein said heterocyclic groups are selected from the group consistingof morpholine, triazole, imidazole, pyrrolidine, piperidine, piperazine,pyrrole, dihydropyridine, aziridine, thiazolidine, thiazoline,thiadiazolidine, and thiadiazoline.
 5. A method of treating diabetes,atherosclerosis, hypercholesterolemia, or hyperlipidemia comprising theadministration of a therapeutically effective amount of the compositioncomprising a carrier and a compound comprising

wherein: A and B may be the same or different and are CH₂, CO, N, NO,NH, SO₀₋₂, or O; D₁-D₆ can be the same or different and are CH, N, S, orO; E can be a substituent attached to one or more of the atoms locatedat D₁-D₆; P and Q can be a double bond; or P, Q, and E can be the sameor different and are a moiety selected from the group consisting of H,C₁₋₁₀ alkyl, substituted alkyl groups, substituted or unsubstitutedcarboxylic acids, substituted or unsubstituted carboxylic esters,halogen, carboxyl, hydroxyl, phosphate, phosphonate, aryl, CN, OH, COOH,NO₂, NH₂, SO₂₋₄, C₁₋₂₀ heteroalkyl, C₂₋₂₀ alkenyl, alkynyl, akynyl-aryl,alkynyl-heteroaryl, aryl, C₁₋₂₀ alkyl-aryl, C₂₋₂₀ alkenyl-aryl,heteroaryl, C₁₋₂₀ alkyl-heteroaryl, C₂₋₂₀ alkenylheteroaryl, cycloalkyl,heterocycloalkyl, C₁₋₂₀ alkyl-heteroycloalkyl, and C₁₋₂₀alkylcycloalkyl, any of which may be, optionally, substituted with amoiety selected from the group consisting of C₁₋₆ alkyl, halogen, OH,NH₂, CN, NO₂, COOH, or SO₂₋₄; X is —OH, —COOH, or a substitutedcarboxylic group comprising OOC— or COO— and said substituted carboxylicgroup is attached to D₁; and analogs, derivatives, or salts thereof. 6.The method according to claim 5, wherein said carrier is apharmaceutically acceptable carrier.
 7. The method according to claim 5,wherein A is NH; B is sulfur (S); P and Q are a double bond or hydrogen(H); E is hydrogen (H) and is attached to each of D₁ through D₆; D₁through D₆ are carbon (C).
 8. The method of claim 5, further comprisingthe administration of additional therapeutic agent.